Phenyl substituted cycloalkylamines as monoamine reputake inhibitors

ABSTRACT

Phenyl-substituted cyclohexylamine derivatives and methods for their synthesis and characterization are disclosed. Use of these compounds to treat/prevent neurological disorders as well as methods for their synthesis are set forth herein. Exemplary compounds of the invention inhibit reuptake of endogenous monoamines, such as dopamine, serotonin and norepinephrine (e.g., from the synaptic cleft) and modulate one or more monoamine transporter. Pharmaceutical formulations incorporating compounds of the invention are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/941,242, filed on May 31, 2007, the disclosure of which isincorporated herein by reference in its entirety for all purposes.

FIELD OF THE INVENTION

The invention relates to compounds and compositions for the treatment ofneurological disorders.

BACKGROUND OF THE INVENTION

Psychiatric disorders are pathological conditions of the braincharacterized by identifiable symptoms that result in abnormalities incognition, emotion, mood, or affect. These disorders may vary inseverity of symptoms, duration, and functional impairment. Psychiatricdisorders afflict millions of people worldwide resulting in tremendoushuman suffering and economic burden due to lost productivity anddependent care.

Over the past several decades, the use of pharmacological agents totreat psychiatric disorders has greatly increased, largely due toresearch advances in both neuroscience and molecular biology. Inaddition, chemists have become increasingly sophisticated at creatingchemical compounds that are more effective therapeutic agents with fewerside effects, targeted to correct the biochemical alterations thataccompany mental disorders.

Yet, despite the many advances that have occurred, many psychiatricdiseases remain untreated or inadequately treated with currentpharmaceutical agents. In addition, many of the current agents interactwith molecular targets not involved with the psychiatric disease. Thisindiscriminate binding can result in side effects that can greatlyinfluence the overall outcome of therapy. In some cases the side effectsare so severe that discontinuation of therapy is required.

Depression is an affective disorder, the pathogenesis of which cannot beexplained by any single cause or theory. It is characterized by apersistently low mood or diminished interests in one's surroundings,accompanied by at least one of the following symptoms: reduced energyand motivation, difficulty concentrating, altered sleep and appetite,and at time, suicidal ideation (American Psychiatric Association:Diagnostic and Statistical Manual of Mental Disorders, ed. 4.Washington, American Psychiatric Association, 1994). Major depression isassociated with high rates of morbidity and mortality, with suiciderates of 10-25% (Kaplan H I, Sadock B J (eds): Synopsis of Psychiatry.Baltimore, Williams & Wilkins, 1998, p. 866). Dual reuptake inhibitorsmay also be used to reduce fatigue commonly associated with depression(see, for example, “Bupropion augmentation in the treatment of chronicfatigue syndrome with coexistent major depression episode”Schonfeldt-Lecuona et al., Pharmacopsychiatry 39(4):152-4, 2006;“Dysthymia: clinical picture, extent of overlap with chronic fatiguesyndrome, neuropharmalogical considerations, and new therapeutic vistas”Brunello et al., J. Affect. Disord. 52(1-3):275-90, 1999; “Chronicfatigue syndrome and seasonal affective disorder: comorbidity,diagnostic overlap, and implications for treatment” Terman et al., Am.J. Med. 105(3A):115S-124S, 1998).

Depression is believed to result from dysfunction in the noradrenergicor serotonergic systems, more specifically, from a deficiency of certainneurotransmitters (NTs) at functionally important adregnergic orserotonergic receptors.

Neurotransmitters produce their effects as a consequence of interactionswith specific receptors. Neurotransmitters, including norepinephrine(NE) and/or serotonin (5-hydroxytryptamine, or 5-HT), are synthesized inbrain neurons and stored in vesicles. Upon a nerve impulse, NTs arereleased into the synaptic cleft, where they interact with variouspostsynaptic receptors. Regional deficiencies in the synaptic levels of5-HT and/or NE are believed to be involved in the etiology ofdepression, wakefulness, and attention.

Norepinephrine is involved in regulating arousal, dreaming, and moods.Norepinephrine can also contribute to the regulation of blood pressure,by constricting blood vessels and increasing heart rate.

Scrotonin (5-HT) is implicated in the etiology or treatment of variousdisorders. The most widely studied effects of 5-HT are those on the CNS.The functions of 5-HT are numerous and include control of appetite,sleep, memory and learning, temperature regulation, mood, behavior(including sexual and hallucinogenic behavior), cardiovascular function,smooth muscle contraction, and endocrine regulation. Peripherally, 5-HTappears to play a major role in platelet homeostasis and motility of theGI tract. The actions of 5-HT are terminated by three major mechanisms:diffusion; metabolism; and reuptake. The major mechanism by which theaction of 5-HT is terminated is by reuptake through presynapticmembranes. After 5-HT acts on its various postsynaptic receptors, it isremoved from the synaptic cleft back into the nerve terminal through anuptake mechanism involving a specific membrane transporter in a mannersimilar to that of other biogenic amines. Agents that selectivelyinhibit this uptake increase the concentration of 5-HT at thepostsynaptic receptors and have been found to be useful in treatingvarious psychiatric disorders, particularly depression.

Approaches to the treatment of depression over the years have involvedthe use of agents that increase the levels of NE and 5-HT, either byinhibiting metabolism (e.g., monoamine oxidase inhibitors) or reuptake(e.g., tricyclic antidepressants or selective serotonin reuptakeinhibitors (SSRISs)).

There are more than twenty approved antidepressant drugs available inthe United States. The classical tricylic antidepressants (TCAs)currently available block primarily the uptake of NE and also, tovarying degrees, the uptake of 5-HT, depending on whether they aresecondary or tertiary amines. Tertiary amines such as imipramine andamitriptyline are more selective inhibitors of the uptake of 5-HT thanof catecholamines, compared with secondary amines such as desipramine.

Selective serotonin reuptake inhibitors have been investigated aspotential antidepressants. Fluoxetine (PROZAC®), sertraline (ZOLOFT®),and paroxetine (PAXIL®) are three examples of SSRIs currently on theU.S. market. These agents do not appear to possess greater efficacy thanthe TCAs, nor do they generally possess a faster onset of action;however, they do not have the advantage of causing less side-effects. Ofthese three SSRIs, paroxetine is the most potent inhibitor of 5-HTuptake, fluoxetine the least. Sertaline is the most selective for 5-HTversus NE uptake, fluoxetine the least selective. Fluoxetine andsertraline produce active metabolites, while paroxetine is metabolizedto inactive metabolites. The SSRIs, in general, affect only the uptakeof serotonin and display little or no affinity for various receptorsystems including muscarinic, adregnergic, dopamine, and histaminereceptors.

In addition to treating depression, several other potential therapeuticapplications for SSRIs have been investigated. They include treatment ofAlzheimer's disease, aggressive behavior, premenstrual syndrome,diabetic neuropathy, chronic pain, fibromyalgia, and alcohol abuse. Forexample, fluoxetine is approved for the treatment ofobsessive-compulsive disorder (OCD). Of particular significance is theobservation that 5-HT reduces food consumption by increasingmeal-induced satiety and reducing hunger, without producing thebehavioral effects of abuse liability associated with amphetamine-likedrugs. Thus, there is interest in the use of SSRIs in the treatment ofobesity.

Venlafaxine (EFFEXOR®) is a dual-reuptake antidepressant that differsfrom the classical TCAs and the SSRIs chemically and pharmalogically inthat it acts as a potent inhibitor of both 5-HT and NE uptake. Neithervenlafaxine nor its major metabolite have a significant affinity foradrenergic alpha-1 receptors. Venlafaxine possesses an efficacyequivalent to that of the TCAs, and a benign side effect profile similarto those of the SSRIs.

Dopamine is hypothesized to play a major role in psychosis and certainneurodegenerative diseases, such as Parkinson's disease, where adeficiency in dopaminergic neurons is believed to be the underlyingpathology. Dopamine affects brain processes that control movement,emotional response, and ability to experience pleasure and pain.Regulation of DA plays a crucial role in our mental and physical health.Certain drugs increase DA concentrations by preventing DA reuptake,leaving more DA in the synapse. An example is methylphenidate(RITALIN®), used therapeutically to treat childhood hyperkinesias andsymptoms of schizophrenia. Dopamine abnormalities are believed tounderlie some of the core attentional abnormalities seen in acuteschizophrenics.

A therapeutic lag is associated with the use of these drugs. Patientsmust take a drug for at least three (3) weeks before achievingclinically meaningful symptom relief. Furthermore, a significant numberof patients do not respond to current therapies at all. For example, itis currently estimated that up to thirty percent (30%) of clinicallydiagnosed cases of depression are resistant to all forms of current drugtherapy.

SUMMARY OF THE INVENTION

The present invention relates to novel cycloalkylamines and saltsthereof. It also relates to novel pharmaceutically compositions, andtheir use in the treatment of disorders and conditions. Exemplaryindications, for the compounds of the invention include neurologicaldisorders such as depression (e.g., major depressive disorder, bipolardisorder), fibromyalgia, pain (e.g., neuropathic pain), sleep apnea,attention deficit disorder (ADD), attention deficit hyperactivitydisorder (ADHD), restless leg syndrome, schizophrenia, anxiety,obsessive compulsive disorder, posttraumatic stress disorder, seasonalaffective disorder (SAD), premenstrual dysphoria as well asneurodegenerative disease (e.g., Parkinson's disease, Alzheimer'sdisease). The compounds of the invention are also of use to treat orprevent obesity or to treat substance abuse, dependency or addiction,including but not limited to nicotine and cocaine abuse, dependency oraddiction.

Hence, in a first aspect the invention provides a compound having theformula:

wherein the index n is an integer selected from the group consisting of0 to 2; and s is an integer selected from the group consisting of 0 to2. A is a member selected from the group consisting of H, substituted orunsubstituted alkyl, halogen and substituted or unsubstituted haloalkyl.X is a member selected from the group consisting of H, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted haloalkyl and OR⁵, in which R⁵ is a memberselected from the group consisting of H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, acyl andS(O)₂R^(5a), in which R^(5a) is a member selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteraryl and substituted or unsubstitutedheterocycloalkyl.

Y and Z are members independently selected from the group consisting ofhalogen, CF₃, CN, OR⁹, SR⁹, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocycloalkyl, NR¹⁰R¹¹ and NO₂, R⁹ represents H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. The radicals R¹⁰ and R¹¹ independently represent H,OR¹², acyl, S(O)₂R¹³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. R¹⁰ and R¹¹, together with the nitrogen to which theyare attached, are optionally joined to form a 3- to 7-membered ring,optionally having from 1 to 3 heteroatoms in addition to the nitrogen towhich R¹⁰ and R¹¹ are joined.

The symbol R¹² is a member selected from H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl orsubstituted or unsubstituted heterocycloalkyl. R¹³ is a member selectedfrom substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

Y and Z, together with the atoms to which they are attached, areoptionally joined to form a 5- to 7-membered ring, which can optionallyhave from 1 to 3 heteroatoms therein. As will be apparent to those ofskill in the art, when Y and Z are joined into a ring, the substituents(e.g., R⁹, R¹⁰ and R¹¹) on atoms incorporated into the ring will bepresent (e.g., incorporated into the cyclic structure of the ring) orabsent as necessary to satisfy the valence of the atom to which thesesubstituents are attached.

R¹ and R² are members independently selected from H, halogen, CN, CF₃,OR⁶, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. R⁶ is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or substituted or unsubstituted heterocycloalkyl.

R³ and R⁴ are members independently selected from H, OR⁷, acyl S(O)₂R⁸,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. R⁷ is a member selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or substituted or unsubstituted heterocylcoalkyl. R⁸ is amember selected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocylcoalkyl.

Two or more of R¹, R², R³ and R⁴, together with the atoms to which theyare attached, are optionally joined to form a 3- to 7-membered ring,which optionally includes from 1 to 4, preferably from 1 to 3heteroatoms.

Any pharmaceutically acceptable salt, solvate, enantiomer, diastereomer,racemic mixture, enantiomerically enriched mixture, and enantiomericallypure form of the above described compounds falls within the scope of theinvention.

In a second aspect, the invention provides a pharmaceutical compositionincluding a compound of the invention or a pharmaceutically acceptablesalt or solvate thereof, and a pharmaceutically acceptable carrier.

In a third aspect, the invention provides a method of inhibiting bindingof a monoamine transporter ligand to a monoamine transporter, such asserotonin transporter, dopamine transporter and norepinephrinetransporter. The method includes contacting the monoamine transporterand a compound of the invention. In an exemplary embodiment themonoamine transporter ligand is a monoamine, such as serotonin, dopamineand norepinephrine.

In a fourth aspect, the invention provides a method of inhibiting theactivity of at least one monoamine transporter, such as serotonintransporter, dopamine transporter and norepinephrine transporter. Themethod includes contacting the monoamine transporter and a compound ofthe invention.

In another aspect, the invention provides a method of inhibiting uptakeof at least one monoamine, such as serotonin, dopamine andnorepinephrine, by a cell. The method includes contacting the cell witha compound of the invention. In an exemplary embodiment, the cell is abrain cell, such as a neuronal cell or a glial cell.

In yet another aspect, the invention provides a method of treatingdepression by inhibiting the activity at least one monoaminetransporter. The method includes administering to a mammalian subject acompound of the invention. In an exemplary embodiment, the compound ofthe invention inhibits the activity of at least two different monoaminetransporters. In another preferred embodiment, the mammalian subject isa human.

In a further aspect, the invention provides a method of treating aneurological disorder. The method includes administering to a subject inneed thereof a therapeutically effective amount of a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof. Inan exemplary embodiment, the subject is a human.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1(A-G) is a table of exemplary compounds of the invention.

FIG. 2 is a graph showing effect of a compound 4 on baseline locomotoractivity in the reserpinized rat.

FIG. 3 is a graph showing effect of compound 4 on rotarod performance inthe reserpinized rat.

FIG. 4 is a graph showing effect of compound 4 on catalepsy in thereserpinized rat.

FIG. 5 is a graph showing combined compound 4 and low does L-DOPArotarod performance as compared to high dose L-DOPA.

FIG. 6 is a graph showing the effect of combination of L-DOPA andcompound 4 in the 6-OHDA lesioned rat.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight or branched chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, unsaturated, e.g., mono- or polyunsaturated and can includedi- and multivalent radicals. Alkyl radicals are optionally designatedas having a number of carbons with a stated range—i.e., C₁-C₁₀ means asubstituted or unsubstituted alkyl moiety having from one to tencarbons. Examples of saturated hydrocarbon radicals include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, see-butyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl; cyclic alkyl, e.g., cyclohexyl,(cyclohexyl)methyl, cyclopropylmethyl, fused ring species including,e.g., fused cycloalkyl (e.g., decalin) and the like. An unsaturatedalkyl group is one having one or more double bonds or triple bonds,e.g., “alkenyl” and “alkynyl”. Examples of unsaturated alkyl groupsinclude, but are not limited to, vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “alkyl,” unless otherwise noted, is also meant toinclude those derivatives of alkyl defined in more detail below, such as“heteroalkyl.” Alkyl groups that are limited to hydrocarbon groups aretermed “homoalkyl”. Exemplary substituents found on “substituted alkyl”moieties are set forth below.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, is a subgenus of “alkyl” as set forthabove, a straight or branched chain, or cyclic alkyl radical, orcombinations thereof, saturated or unsaturated alkyl radical consistingof a number of carbon atoms (optionally stated) and at least oneheteroatom, preferably selected from B, O, N, P, Si and S, and whereinthe nitrogen and sulfur atoms may optionally be oxidized and thenitrogen heteroatom may optionally be quaternized. The heteroatom(s) B,O, N, P, Si and S may be at any internal position of the heteroalkylgroup or at the position at which the heteroalkyl group is attached tothe remainder of the molecule, or at the antipodal terminus thereof.Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃,—CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Two or more heteroatoms may beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.Similarly, the term “heteroalkylene” by itself or as part of anothersubstituent means a divalent radical derived from heteroalkyl, asexemplified, but not limited by, —CH₂—CH₃—S—CH₃—CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylene groups, heteroatoms can alsooccupy either or both of the chain termini (e.g., alkyleneoxy,alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Stillfurther, for alkylene and heteroalkylene linking groups, no orientationof the linking group is implied by the direction in which the formula ofthe linking group is written. For example, the formula —CO₂R′—optionally represents both —C(O)OR′ and —OC(O)R′.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” is mean to include, but not be limited to,trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, substituent that can be a single ring or multiple rings(preferably from 1 to 3 rings), which are fused together or linkedcovalently. “Aryl” species include structures that include aryl ringsfused with cycloalkyl, heterocycloalkyl and heteroaryl rings. The term“heteroaryl” is subgeneric to “aryl” and refers to aryl groups thatcontain from one to four heteroatoms, preferably selected from B, O, N,P, Si and S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized. Aheteroaryl group can be attached to the remainder of the moleculethrough a heteroatom. Non-limiting examples of aryl and heteroarylgroups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl,2-pyrrolyl, 3-pyrrolyl, 3-pyrzaolyl, 2-imidazolyl, 4-imidazolyl,pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenly-4-oxazolyl, 5-oxazolyl,3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl,purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl,2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituentsfor each of the above noted aryl and heteroaryl ring systems areselected from the group of acceptable substituents described below.

For brevity, the term “aryl” when used to define a substituent (e.g.,aryloxy, arylthioxy, arylalkyl) optionally includes both aryl andheteroaryl rings as defined above. Thus, the term “arylalkyl” is meantto include those radicals in which an aryl group is attached to an alkylgroup (e.g., benzyl, phenethyl, pyridylmethyl and the like) includingthose alkyl groups in which a carbon atom (e.g., a methylene group) hasbeen replaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) are meant to include both substituted and unsubstitutedforms of the indicated radical. Preferred substituents for each type ofradical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) are generically referred to as “alkyl groupsubstituents,” and they can be one or more of a variety of groupsselected from, but not limited to: substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted heterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂ in a number preferably ranging from zero to (2m′+1), where m′ isthe total number of carbon atoms in such radical. R′, R″, R′″ and R″″each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl, e.g., arylsubstituted with 1-3 halogens, substituted or unsubstituted alkyl,alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 5-, 6-, or 7-membered ring. for example —NR′R″is meant to include, but not be limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are generically referredto as “aryl group substituents.” The substituents are selected from, forexample: substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halogen,—SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CNR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂, —R′, —N₃,—CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl, in a numberranging from zero to the total number of open valences on the aromaticring system; and where R′, R″, R′″ and R″″ are preferably independentlyselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted heteroalkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula—T—C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′— or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —A—(CH₂)₅—D—, wherein A and D are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′— or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′_(s)—X″—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X″ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituent R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆)alkyl.

As used herein, the term “acyl” described a substituent containing acarbonyl residue, C(O)R. Exemplary species for R include H, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocylcloalkyl.

As used herein, the term “fused ring system” means at least two rings,wherein each ring has at least 2 atoms in common with another ring.“Fused ring systems may include aromatic (i.e., aryl or heteroaryl) aswell as saturated or unsaturated non aromatic rings (i.e., cycloalkyl,heterocycloalkyl). Examples of “fused ring systems” are naphthalenes,indoles, quinolines, chromenes, decalin and the like.

As used herein, the term “heteroatom” includes oxygen (O), nitrogen (N),sulfur (S), silicon (Si), boron (B), and phosphorus (P).

The symbol “R” is a general abbreviation that represents an “alkyl groupsubstituent” or “aryl group substituent” (e.g., a substituent group thatis selected from substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, and substituted orunsubstituted heterocycloalkyl groups).

The phrase “therapeutically effective amount” as used herein means thatamount of a compound, or composition comprising a compound of thepresent invention which is effective for producing some desiredtherapeutic effect (e.g., by inhibiting uptake of a monoamine from thesynaptic cleft of a mammal, thereby modulating the biologicalconsequences of the pathway in the treated organism) at a reasonablebenefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in humanbeings and animals without excessive toxicity, irritation, allergicresponse, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable carrier” as used herein meansany pharmaceutically acceptable material, which may be liquid or solid.Exemplary carriers include vehicles, diluents, additives, liquid andsolid fillers, excipients, solvents, solvent encapsulating materials.Each carrier must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and into injurious to thepatient. Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) pH buffered solutions; (21)polyesters, polycaronates and/or polyanhydrides; and (22) othernon-toxic compatible substances employed in pharmaceutical formulations.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, and are,thus, capable of forming pharmaceutically acceptable salts withpharmaceutically acceptable acids. The term “pharmaceutically acceptablesalts” in this respect, refers to the relatively non-toxic, inorganicand organic acid addition salts of compounds of the present invention.These salts can be prepared in situ in the administration vehicle or thedosage form manufacturing process, or by separately reacting a purifiedcompound of the invention in its free base form with a suitable organicor inorganic acid, and isolating the salt thus formed during subsequentpurification. Representative salts include the hydrobromide,hydrochloride, sulfate, sulfamate, bisulfate, phosphate, nitrate,acetate, valerate, oleate, palmitate, stearate, laurate, benzoate,lactate, tosylate, citrate, maleate, ascorbate, palmitate, furmarate,succinate, tartrate, napthylate, mesylate, hydroxymaleate,phenylacetate, glutamate, glucoheptonate, salicyclate, sulfanilate,2-acetoxybenzoate, methanesulfonate, ethane disulfonate, oxalateisothionate, lactobionate, and laurylsulphonate salts and the like. See,for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.

The term “pharmaceutically acceptable salts” includes salts of theactive compounds which are prepared with relatively nontoxic acids orbases, depending on the particular substituents found on the compoundsdescribed herein. When compounds of the present invention containrelatively acidic functionalities, base addition salts can be obtainedby contacting the neutral form of such compounds with a sufficientamount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts includesodium, potassium, calcium, ammonium, organic amino, or magnesium salt,or a similar salt. When compounds of the present invention containrelatively basic functionalities, acid addition salts can be obtained bycontacting the neutral form of such compounds with a sufficient amountof the desired acid, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable acid addition salts includethose derived from inorganic acids like hydrochloric, hydrobromic,nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., Journal of Pharmaceutical Science,66: 1-19 (1977)). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention. “Compound or a pharmaceutically acceptable salt orsolvate of a compound” intends the inclusive meaning of “or”, in that amaterial that is both a salt and a solvate is encompassed.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention. Optically active (R)- and (S)-isomersmay be prepared using chiral synthons or chiral reagents, or resolvedusing conventional techniques. When the compounds described hereincontain olefinic double bonds or other centers of geometric asymmetry,and unless specified otherwise, it is intended that the compoundsinclude both E and Z geometric isomers. Likewise, all tautomeric formsare also intended to be included.

The graphic representations of racemic, ambiscalemic and scalemic orenantiomerically pure compounds used herein are taken from Maehr, J.Chem. Ed., 62: 114-120 (1985): wavy lines indicate disavowal of anystereochemical implication which the bond it represents could generate;solid and broken wedges are geometric descriptors indicating therelative configuration shown but not implying any absolutestereochemistry; and wedge outlines and dotted or broken lines denoteenantiomerically pure compounds of indeterminate absolute configuration.

The terms “enantiomeric excess” and “diastereomeric excess” are usedinterchangeably herein. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess,” those with atleast two stereocenters are referred to as being present in“diastereomeric excess.”

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The term “monoamine transporter ligand” refers to any compound, whichbinds to a monoamine transporter. Ligands include endogenous monoamines,which are the natural ligands for a given monoamine transporter as wellas drug molecules and other compounds, such as synthetic molecules knownto bind to a particular monoamine transporter. In one example, theligand includes a radioisotope, such as tritium or is otherwise (e.g.,fluorescently) labeled. It is within the abilities of the skilled personto select an appropriate ligand for a given monoamine transporter. Forexample, known ligands for the dopamine transporter include dopamine andWIN35428, known ligands for the serotonin transporter include5-hydroxytryptamine (serotonin) and citalopram, and ligands for thenorepinephrine transporter include norepinephrine and nisoxetine.

The term “eating disorder” refers to abnormal compulsions to avoideating or uncontrollable impulses to consume abnormally large amounts offood. These disorders affect not only the social well-being, but alsothe physical well-being of sufferers. Examples of eating disordersinclude anorexia nervosa, bulimia, and binge eating.

The term “neurological disorder” refers to any condition of the centralor peripheral nervous system of a mammal. The term “neurologicaldisorder” includes a neurodegenerative diseases (e.g., Alzheimer'sdisease, Parkinson's disease and amyotrophic lateral sclerosis),neuropsychiatric diseases (e.g., schizophrenia and anxieties, such asgeneral anxiety disorder). Exemplary neurological disorders include MLS(cerebellar ataxia), Huntington's disease, Down syndrome, multi-infaretdementia, status epilecticus, contusive injuries (e.g. spinal cordinjury and head injury), viral infection induced neurodegeneration,(e.g. AIDS, encephalopathies), epilepsy, benign forgetfulness, closedhead injury, sleep disorders, depression (e.g., bipolar disorder),dementias, movement disorders, psychoses, alcoholism, post-traumaticstress disorder and the like. “Neurological disorder” also includes anycondition associated with the disorder. For instance, a method oftreating a neurodegnerative disorder includes methods of treating lossof memory and/or loss of cognition associated with a neurodegenerativedisorder. An exemplary method would also include treating or preventingloss of neuronal function characteristic of neurodegenerative disorder.“Neurological disorder” also includes any disease or condition that isimplicated, at least in part, in monamine (e.g., norepinephrine)signaling pathways (e.g., cardiovascular disease).

“Pain” is an unpleasant sensory and emotional experience. Painclassifications have been based on duration, etiology orpathophysiology, mechanism, intensity, and symptoms. The term “pain” asused herein refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic peripheral neuropathic pain (see, e.g.,Harrison's Principles of Internal Medicine, pp. 93-98 (Wilson et al.,eds., 12th ed. 1991); Williams et al., J. of Med. Chem. 42: 1481-1485(1999), herein each incorporated by reference in their entirety). “Pain”is also meant to include mixed etiology pain, dual mechanism pain,allodynia, causalgia, central pain, hyperesthesia, hyperpathia,dysesthesia, and hyperalgesia.

“Somatic” pain, as described above, refers to a normal nerve response toa noxious stimulus such as injury or illness, e.g., trauma, burn,infection, inflammation, or disease process such as cancer, and includesboth cutaneous pain (e.g., skin, muscle or joint derived) and visceralpain (e.g., organ derived).

“Neuropathic pain” is a heterogeneous group of neurological conditionsthat result from damage to the nervous system. “Neuropathic” pain, asdescribed above, refers to pain resulting from injury to or dysfunctionsof peripheral and/or central sensory pathways, and from dysfunctions ofthe nervous system, where the pain often occurs or persists without anobvious noxious input. This includes pain related to peripheralneuropathies as well as central neuropathic pain. Common, types ofperipheral neuropathic pain include diabetic neuropathy (also calleddiabetic peripheral neuropathic pain, or DN, DPN, or DPNP),post-herpetic peuralgia (PHN), and trigeminal neuralgia (TGN). Centralneuropathic pain, involving damage to the brain or spinal cord, canoccur following stroke, spinal cord injury, and as a result of multiplesclerosis. Other types of pain that are meant to be included in thedefinition of neuropathic pain include pain from neuropathic cancerpain, HIV/AIDS induced pain, phantom limb pain, and complex regionalpain syndrome. In an exemplary embodiment, the compounds of theinvention are of use for treating neuropathic pain.

Common clinical features of neuropathic pain include sensory loss,allodynia (non-noxious stimuli produce pain), hyperalgesia andhyperpathia (delayed perception, summation, and painful aftersensation).Pain is often a combination of nociceptive and neuropathic types, forexample, mechanical spinal pain and radiculopathy or myelopathy.

“Acute pain”, is the normal, predicted physiological response to anoxious chemical, thermal or mechanical stimulus typically associatedwith invasive procedures, trauma and disease. It is generallytime-limited, and may be viewed as an appropriate response to a stimulusthat threatens and/or produces tissue injury. “Acute pain”, as describedabove, refers to pain which is marked by short duration or sudden onset.

“Chronic pain” occurs in a wide range of disorders, for example, trauma,malignancies and chronic inflammatory diseases such as rheumatoidarthritis. Chronic pain usually lasts more than about six months. Inaddition, the intensity of chronic pain may be disproportionate to theintensity of the noxious stimulus or underlying process. “Chronic pain”,as described above, refers to pain associated with a chronic disorder,or pain that persists beyond resolution of an underlying disorder orhealing of an injury, and that is often more intense than the underlyingprocess would predict. It may be subject to frequent recurrence.

“Inflammatory pain” is pain in response to tissue injury and theresulting inflammatory process. Inflammatory pain is adaptive in that itelicits physiologic responses that promote healing. However,inflammation may also affect neuronal function. Inflammatory mediators,including PGE₂ induced by the COX2 enzyme, bradykinins, and othersubstances, bind to receptors on pain-transmitting neurons and altertheir function, increasing their excitability and thus increasing painsensation. Much chronic pain has an inflammatory component.“Inflammatory pain”, as described above, refers to pain which isproduced as a symptom or a result of inflammation or an immune systemdisorder.

“Visceral pain”, as described above, refers to pain which is located inan internal organ.

“Mixed etiology” pain, as described above, refers to pain that containsboth inflammatory and neuropathic components.

“Dual mechanism” pain, as described above, refers to pain that isamplified and maintained by both peripheral and central sensitization.

“Causalgia”, as described above, refers to a syndrome of sustainedburning, allodynia, and hyperpathia after a traumatic nerve lesion,often combined with vasomotor and sudomotor dysfunction and latertrophic changes.

“Central” pain, as described above, refers to pain initiated by aprimary lesion or dysfunction in the central nervous system.

“Hyperesthesia”, as described above, refers to increased sensitivity tostimulation, excluding the special senses.

“Hyperpathia”, as described above, refers to a painful syndromecharacterized by an abnormally painful reaction to a stimulus,especially a repetitive stimulus, as well as an increased threshold. Itmay occur with allodynia, hyperesthesia, hyperalgesia, or dysesthesia.

“Dysesthesia”, as described above, refers to an unpleasant abnormalsensation, whether spontaneous or evoked. Special cases of dysesthesiainclude hyperalgesia and allodynia.

“Hyperalgesia”, as described above, refers to an increased response to astimulus that is normally painful. It reflects increased pain onsuprathreshold stimulation.

“Allodynia”, as described above, refers to pain due to a stimulus thatdoes not normally provoke pain.

The term “pain” includes pain resulting from dysfunction of the nervoussystem: organic pain states that share clinical features of neuropathicpain and possible common, pathophysiology mechanisms, but are notinitiated by an identifiable lesion in any part of the nervous system.

The term “Diabetic Peripheral Neuropathic Pain” (DPNP, also calleddiabetic neuropathy, DN or diabetic peripheral neuropathy) refers tochronic pain caused by neuropathy associated with diabetes mellitus. Theclassic presentation of DPNP is pain or tingling in the feet that can bedescribed not only as “burning” or “shooting” but also as severe achingpain. Less commonly, patients may describe the pain as itching, tearing,or like a toothache. The pain may be accompanied by allodynia andhyperalgesia and an absence of symptoms, such as numbness.

The term “Post-Herperic Neuralgia”, also called “Postherpetic Neuralgia”(PHN), is a painful condition affecting nerve fibers and skin. It is acomplication of shingles, a second outbreak of the varicella rostervirus (VZV), which initially causes chickenpox.

The term “neuropathic cancer pain” refers to peripheral neuropathic painas a result of cancer, and can be caused directly by infiltration orcompression of a nerve by a tumor, or indirectly by cancer treatmentssuch as radiation therapy and chemotherapy (chemotherapy-inducedneuropathy).

The term “HIV/AIDS peripheral neuropathy” or “HIV/AIDS relatedneuropathy” refers to peripheral neuropathy caused by HIV/AIDS, such asacute or chronic inflammatory demyelinating neuropathy (AIDP and CIDP,respectively), as well as peripheral neuropathy resulting as a sideeffect of drugs used to treat HIV/AIDS.

The term “Phantom Limb Pain” refers to pain appearing to come from wherean amputated limb used to be. Phantom limb pain can also occur in limbsfollowing paralysis (e.g., following spinal cord injury). “Phantom LimbPain” is usually chronic in nature.

The term “Trigeminal Neuralgia” (TN) refers to a disorder of the fifthcranial (trigeminal) nerve that causes episodes of intense, stabbing,electric-shock-like pain in the areas of the face where the branches ofthe nerve are distributed (lips, eyes, nose, scalp, forehead, upper jaw,and lower jaw). It is also known as the “suicide disease”.

The term “Complex Regional Pain Syndrome (CRPS),” formerly known asReflex Sympathetic Dystrophy (RSD), is a chronic pain condition. The keysymptom of CRPS is continuous, intense pain out of proportion to theseverity of the injury, which gets worse rather than better over time.CRPS is divided into type 1, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2, in which the syndrome isprovoked by major nerve injury, and is sometimes called causalgia.

The term “Fibromyalgia” refers to a chronic condition characterized bydiffuse or specific muscle, joint, or bone pain, along with fatigue anda range of other symptoms. Previously, fibromyalgia was known by othernames such as fibrositis, chronic muscle pain syndrome, psychogenicrheumatism and tension myalgias.

The term “convulsion” refers to a neurological disorder and is usedinterchangeably with “seizure,” although there are many types ofseizure, some of which have subtle or mild symptoms instead ofconvulsions. Seizures of all types may be caused by disorganized andsudden electrical activity in the brain. Convulsions are a rapid anduncontrollable shaking. During convulsions, the muscles contract andrelax repeatedly.

The term “depression” includes all forms of depression, which includemajor depressive disorder (MDD), bipolar disorder, seasonal affectivedisorder (SAD) and dysthymia. “Major depressive disorder” is used hereininterchangeably with “unipolar depression” and “major depression.“Depression” also includes any condition commonly associated withdepression, such as all forms of fatigue (e.g., chronic fatiguesyndrome) and cognitive deficits.

II. Introduction

One strategy to develop effective therapies for neurological disordersis the use of broad spectrum antidepressants that simultaneously inhibitthe reuptake of more than one biogenic amine, such as serotonin (5-HT),norepinephrine (NE) and dopamine (DA). The rationale for this approachis based upon clinical and preclinical evidence showing thatdeficiencies in dopaminergic function can be correlated with anhedonia,which is a core symptom of depression. Baldessarini, R. J., “Drugs andthe Treatment of Psychiatric Disorders: Depression and Mania, in Goodmanand Gilman's The Pharmacological Basis of Therapeutics 431-459 (9^(th)ed 1996) Hardman et al. eds.

An advantage of exemplary compounds and compositions of the presentinvention is their ability to increase availability of at least twoneurotransmitters (e.g., NE, 5-HT and DA) by inhibiting their dual(re)uptake, e.g., from the synaptic cleft. Skolnick and coworkers reporton a body of preclinical evidence suggesting that the therapeuticprofile of an antidepressant concurrently increasing the synapticavailability of DA, NE and 5-HT will differ from a compound inhibitingonly NE and/or 5-HT. Skolnick, P. et al., “Antidepressant-like actionsof DOV-21,947: a “triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461,103.

For example, Skolnick and coworkers have reported that a compound, DOV21,947((+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane), inhibitsthe reuptake of serotonin, norepinephrine, and dopamine in humanembryonic kidney (HEK293) cells expressing the corresponding humanrecombinant transporters (IC₅₀ values of 12, 23 and 96 nM,respectively). Skolnick, P, et al., “Antidepressant-like actions ofDOV-21,947: a “triple” reuptake inhibitor,” Eur. J. Pharm. 2003, 461,99. In addition, DOV 21,947 reduces the duration of immobility in theforced swim test (in rats) and also produces a dose-dependent reductionin immobility in the tail suspension test. Additional evidence can befound in preclinical data for new triple reuptake inhibitors such as DOV21,947 in, e.g., U.S. Pat. No. 6,372,919, wherein DOV 21,947 wasdisclosed as having a significantly greater affinity for thenorepinephrine and serotonin uptake sites than the racemic compound,(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane.

Taken together, the preclinical data for compounds such as DOV 21,947indicate that dual or triple reuptake inhibitors hold potential as noveltreatments for depression in the clinic.

III. Compositions A. Cycloalkyl Amines

In an exemplary embodiment, the invention provides a compound having theformula:

wherein the index n is an integer selected from the group consisting of0, 1 and 2; and s is an. integer selected from the group consisting of0, 1 and 2. A is a member selected from H, substituted or unsubstitutedalkyl, halogen and substituted or unsubstituted haloalkyl. X is selectedfrom H, halogen, substituted or nonsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted haloalkyl and OR⁵, inwhich R⁵ is selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, acyl and S(O)₂R^(5a), inwhich R^(5a) is selected from substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl and substituted orunsubstituted heterocycloalkyl.

Y and Z independently represent H, halogen, CF₃, CN, OR⁹, SR⁹,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl,NR¹⁰R¹¹ or NO₂. Y and Z, together with the atoms to which they areattached, are optionally joined to form a 5- to 7-membered ring, whichcan optionally have 1, 2 or 3 heteroatoms therein. R⁹ represents H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or substituted or unsubstitutedheterocycloalkyl. The radicals R¹⁰ and R¹¹ independently represent H,OR¹², acyl, S(O)₂R¹³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. R¹⁰ and R¹¹, together with the nitrogen to which theyare attached, are optionally joined to form a 3-, 4-, 5- 6- or7-membered ring, optionally having 1, 2 or 3 heteroatoms in addition tothe nitrogen to which R¹⁰ and R¹¹ are joined. The symbol R¹² representsH, substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. R¹³ is selected from substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl andsubstituted or unsubstituted heterocycloalkyl.

R¹ and R² are independently H, halogen, CN, CF₃, OR6, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or substituted or unsubstituted heterocycloalkyl. R⁶ isselected from H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl.

R3 and R4 independently represent H, OR⁷, acyl, S(O)₂R⁸, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl or substituted or unsubstituted heterocycloalkyl. R⁷ is H,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl or substituted or unsubstitutedheterocycloalkyl. R⁸ is a member selected from substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl.

Two or more of R¹, R², R³ and R⁴, together with the atoms to which theyare attached, are optionally joined to form a 3-, 4-, 5-, 6- or7-membered ring, which optionally includes 1, 2, 3 or 4 heteroatoms.

Y and Z, together with the atoms to which they are attached, areoptionally joined to form a 5-, 6- or 7-membered ring, which canoptionally have 1, 2 or 3 heteroatoms therein. As will be apparent tothose of skill in the art, when Y and Z are joined into a ring, thesubstituents (e.g., R⁹, R¹⁰ and R¹¹) on atoms incorporated into the ringwill be present (e.g., incorporated into the cyclic structure of thering) or absent as necessary to satisfy the valence of the atom to whichthese substituents are attached.

In an exemplary embodiment, Y and Z independently represent halogen,CF₃, CN, OR⁹, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocycloalkyl, NR¹⁰R¹¹ and NO₂. Y and Z, together with the atoms towhich they are attached, are optionally joined to form a 6- or7-membered ring, which can optionally have 1, 2 or 3 heteroatomstherein.

In an exemplary embodiment, the compound of the invention does not havea structure according to the following formula:

In another exemplary embodiment, the compound does not have a structureaccording to the following formula:

In an exemplary embodiment, the compound has a structure such that wheneither Y or Z is H, then R⁹ is other than a member selected from H andsubstituted or unsubstituted alkyl. In an exemplary embodiment, thecompound has a structure such that when either Y or Z is H, then R⁹ isother than a member selected from H and unsubstituted alkyl. In anexemplary embodiment, the compound has a structure such that when eitherY or Z is H, then R⁹ is other than a member selected from H, methyl orethyl.

In an exemplary embodiment, the compound has a structure such that R⁵ isother than a member selected from H and substituted or unsubstitutedalkyl. In an exemplary embodiment, the compound has a structure suchthat R⁵ is other than a member selected from H and unsubstituted alkyl.In an exemplary embodiment, the compound has a structure such that R⁵ isother than a member selected from H, methyl and ethyl.

In various exemplary embodiments, the index s is 1. In an exemplaryembodiment, the index n is 1. In various embodiments, both s and n are1.

In an exemplary embodiment, Y and Z are independently selected from H,halogen, CN and CF₃. In various embodiments, at least one of Y and Z isother than H. In exemplary embodiments, both Y and Z are other than H.

In an exemplary embodiment, R³ and R⁴ are members independently selectedfrom substituted or unsubstituted C₁-C₄ alkyl and substituted orunsubstituted C₁-C₄ heteroalkyl. In an exemplary embodiment, R³ and R⁴are members independently selected from the group consisting ofsubstituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl and substituted or unsubstituted cycloalkyl.

In various embodiments, the compounds of the invention have a structurewhich is a member selected from the group consisting of:

In selected embodiments, the compounds of the invention have a structureselected from Formulae II and IIa:

Exemplary compounds according to Formulae II and IIa include:

In an exemplary embodiment, Y and Z are members independently selectedfrom the group consisting of H, halogen, CN and CF₃. In an exemplaryembodiment, Y and Z are halogen. In an exemplary embodiment, Y and Z arechloro. In an exemplary embodiment, s is 1. In an exemplary embodiment,n is 1. In an exemplary embodiment, R⁵ and R² are H. In an exemplaryembodiment, A is H. In another exemplary embodiment, R¹ and R² are H,and A is H.

In selected embodiments, the compounds of the invention have a structureselected from Formulae III and IIIa:

Exemplary compounds according to Formulae III and IIIa include:

In an exemplary embodiment, Y and Z are members independently selectedfrom the group consisting of H, halogen, CN and CF₃. In an exemplaryembodiment, Y and Z are halogen. In an exemplary embodiment, Y and Z arechloro. In an exemplary embodiment, s is 1. In an exemplary embodiment,n is 1. In an exemplary embodiment, R¹ and R² are H. In an exemplaryembodiment, A is H. In another exemplary embodiment, R¹ and R² are H,and A is H.

In an exemplary embodiment, the compound has a structure according toFormula (IV):

wherein Y and Z are independently selected halogens. In an exemplaryembodiment, the compounds have a structure according to:

In an exemplary embodiment, the compounds have a structure according to:

In another embodiment, Y is a member selected from F and Cl. In anotherembodiment, Z is a member selected from F and Cl. In another embodiment,Y is Cl and Z is Cl. In another embodiment, Y is F and Z is Cl. Inanother embodiment, Y is Cl and Z is F.

In an exemplary embodiment, the compound has a structure according toFormula (V):

wherein Y and Z are independently selected halogens. In an exemplaryembodiment, the compounds have a structure according to:

In an exemplary embodiment, the compounds have a structure according to:

In another embodiment, Y is a member selected from F and Cl. In anotherembodiment, Z is a member selected from F and Cl. In another embodiment,Y is Cl and Z is Cl. In another embodiment Y is F and Z Is Cl. Inanother embodiment, Y is Cl and Z is F.

An exemplary compound of the invention has the formula:

in which R⁴ is either H or CH₃.

In an exemplary embodiment, the compound has a structure according toFormula (VI):

In another exemplary embodiment, the compound having this structure hasat least one member selected from Y and Z which is a halogen. In anotherexemplary embodiment, Y and Z are halogen. In another embodiment, Y is amember selected from F and Cl. In another embodiment, Z is a memberselected from F and Cl. In another embodiment, Y is Cl and Z is Cl. Inanother embodiment, Y is F and Z is Cl. In another embodiment, Y is Cland Z is F.

In an exemplary embodiment, the compound has a structure according toFormula (VII):

wherein Y and Z are not H and A is a member selected from substituted orunsubstituted alkyl. In another exemplary embodiment, the compoundhaving this structure has at least one member selected from Y and Zwhich is a halogen. In another exemplary embodiment, Y and Z arehalogen. In another embodiment, Y is a member selected from F and Cl. Inanother embodiment, Z is a member selected from F and Cl. In anotherembodiment, Y is Cl and Z is Cl. In another embodiment, Y is F and Z isCl. In another embodiment, Y is Cl and Z is F. In an exemplaryembodiment, A is substituted or unsubstituted methyl. In an exemplaryembodiment, A is methyl.

In an exemplary embodiment, the compound has a structure according toFormula (VIII):

wherein Y and Z are not H and R³ and R⁴ are each independently selectedfrom H and substituted or unsubstituted alkyl. In another exemplaryembodiment, R³ and R⁴ are each independently selected from H andsubstituted or unsubstituted methyl. In another exemplary embodiment, R³and R⁴ are each independently selected from H and methyl. In anotherexemplary embodiment, the compound having this structure has at leastone member selected from Y and Z which is a halogen. In anotherexemplary embodiment, Y and Z are halogen. In another embodiment, Y is amember selected from F and Cl. In another embodiment, Z is a memberselected from F and Cl. In another embodiment, Y is Cl and Z is Cl. Inanother embodiment, Y is F and Z is Cl. In another embodiment, Y is Cland Z is F.

Exemplary compounds of the invention have a structure according to thefollowing formulae:

in which A¹, A², A³ and A⁴ are each independently selected from O, S,N(R^(b))_(b), and C(R^(b))_(b)(R^(c)). The index a is an integerselected from 0, 1 and 2. The index b is 0 or 1 as needed to satisfy thevalence requirements of the atom to which it is attached. R^(b) andR^(c) are member independently selected from H, halogen, CF₃, CN, OR¹⁴,SR¹⁴, NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁴, NR¹⁵C(O)R¹⁴, S(O)₂R¹⁴, acyl, C(O)OR¹⁴,C(O)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl and substituted orunsubstituted heterocycloalkyl. Each R¹⁴, R¹⁵ and R¹⁶ is a memberindependently selected from the group consisting of H, acyl, substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycloalkyl, wherein twoof R¹⁴, R¹⁵ and R¹⁶, together with the atoms to which they are attached,are optionally joined to form a 3-, 4-, 5-, 6- or 7-membered ring, whichoptionally includes 1, 2 or 3 heteroatoms.

In an exemplary embodiment, R^(b) and R^(c) are members independentlyselected from the group consisting of H, halogen, CN, halogensubstituted C₁-C₄ alkyl (e.g., CF₃) and C₁-C₄ alkoxy (e.g., OMe, OEt,OCF₃).

In an exemplary embodiment, Y and Z are joined to form a fused ringsystem having 5, 6 or 7 members and, optionally including 1, 2 or 3heteroatoms. Hence, in one embodiment, the phenyl ring substituent hasthe structure:

in which, ring L is substituted or unsubstituted, saturated orunsaturated cycloalkyl or heterocycloalkyl, or it is substituted orunsubstituted aryl or heteroaryl.

An exemplary fused ring structure is:

in which A¹, A², A³ and A⁴ and a are described herein.

The compounds of the invention include an amine moiety (e.g., a primary,secondary or tertiary amino group) and as such can be converted into asalt form by contacting the compound (e.g., the free base) with an acid.In an exemplary embodiment, the salt form is generated to convert anotherwise oily or viscous compound into a solid substance for easierhandling. In another exemplary embodiment, converting the free base of acompound of the invention into a corresponding salt increases solubilityof the compound in aqueous media, which can effect biologicalcharacteristics, such as bioavailability, pharmacokinetics andpharmacodynamics. Hence, any salt forms, such as pharmaceuticallyacceptable salts, including salts of inorganic acids (e.g.,hydrochloride salts) or organic acids, of the compounds of the inventionare within the scope of the current invention. Also within the scope ofthe invention are any prodrugs of the compounds of the invention. Forexample, R³ and R⁴ can be any group, which is cleavable in vivo toresult in an amine, e.g., a primary or secondary amine.

B. Compositions Including Stereoisomers

The compound of the invention can include one or more stereocenter andmay exist in particular geometric or stereoisomeric forms. Compounds canbe chiral, racemic or be present in a composition including one or morestereoisomer. The current invention encompasses enantiomers,diastereomers, racemic mixtures, enantiomerically enriched mixtures, anddiastereomerically enriched mixture. Additional asymmetric carbon atomsmay be present in a substituent such as an alkyl group. All suchisomers, as well as mixtures thereof, are intended to be included inthis invention.

If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivatization with a chiral auxiliary, where the resultingdiastereomeric mixture is separated and the auxiliary group cleaved toprovide the pure desired enantiomers. Alternatively, where the moleculecontains a basic functional group, such as an amino group, or an acidicfunctional group, such as a carboxyl group, diastereomeric salts may beformed with an appropriate optically active acid or base, followed byresolution of the diastereomers thus formed by fractionalcrystallization or chromatographic means known in the art, andsubsequent recovery of the pure enantiomers. In addition, separation ofenantiomers and diastereomers is frequently accomplished usingchromatography employing chiral, stationary phases, optionally incombination with chemical derivatization (e.g., formation of carbamatesfrom amines).

As used herein, the term “enantiomerically enriched” or“diastereomerically enriched” refers to a compound having anenantiomeric excess (ee) or a diastereomeric excess (de) greater thanabout 50%, preferably greater than about 70% and more preferably greaterthan about 90%. In general, higher than about 90% enantiomeric ordiastereomeric purity is particularly preferred, e.g., thosecompositions with greater than about 95%, greater than about 97% andgreater than about 99% ee or de.

The terms “enantiomeric excess” and “diastereomeric excess” are usedinterchangeably herein. Compounds with a single stereocenter arereferred to as being present in “enantiomeric excess”; those with atleast two stereocenters are referred to as being present in“diastereomeric excess”.

For example, the term “enantiomeric excess” is well known in the art andis defined as:

${ee}_{a} = {\left( \frac{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} - {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}}{{{{conc}.\mspace{14mu} {of}}\mspace{14mu} a} + {{{conc}.\mspace{14mu} {of}}\mspace{14mu} b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number of 0 to 100, zero being racemic and 100 beingenantiomerically pure. A compound which in the past might have beencalled 98% optically pure is now more precisely characterized by 96% ee.A 90% ee reflects the presence of 95% of one enantiomer and 5% of theother(s) in the material in question.

Hence, in one embodiment, the invention provides a composition includinga first stereoisomer and at least one additional stereoisomer of acompound of the invention. The first stereoisomer may be present in adiastereomeric or enantiomeric excess of at least about 80%, preferablyat least about 90% and more preferably at least about 95%. In aparticularly preferred embodiment, the first stereoisomer is present ina diastereomeric or enantiomeric excess of as least about 96%, at leastabout 97%, at least about 98%, at least about 99% or at least about99.5%. Enantiomeric or diastereomeric excess may be determined relativeto exactly one other stereoisomer, or may be determined relative to thesum of at least two other stereoisomers. In an exemplary embodiment,enantiomeric or diastereomeric excess is determined relative to allother detectable stereoisomers, which are present in the mixture.Stereoisomers are detectable if a concentration of such stereoisomer inthe analyzed mixture can be determined using common analytical methods,such as chiral HPLC.

C. Synthesis of the Compounds 1. General

Compounds of the invention may be synthesized as pure cis isomers or aracemic mixture, or a mixture of two or more diastereomers.Stereoisomers may be separated at an appropriate synthetic stage, forexample, by chiral column chromatography, such as HPLC to giveenantiomerically/diastereomerically enriched or enantiomerically ordiastereomerically pure forms of the respective stereoisomers.Stereochemical assignments may be made on the basis of NMR couplingpatterns optionally in conjunction with literature values. Absoluteconfigurations can be determined by synthesis from chiral precursor ofknown configuration, or by X-ray crystallographic determination usingcrystallized materials.

Stereochemical-configurations are defined according to the relativeconfiguration of the amine-bearing side chain and the substituent on thecycloalkyl ring. When more than one substituent is present, the higherorder (IUPAC) substituent is used for the determination ofstereochemical-configuration.

Compounds of the invention may be synthesized according to the schemesset forth below. It is within the abilities of a person skilled in theart to select appropriate alternative reagents replacing the exemplaryreagents shown in the schemes in order to synthesize a desired compoundof the invention. It is also within the abilities of a skilled artisanto omit or add synthetic steps when necessary.

2. General Synthesis of Cycloalkylamines

In one embodiment, the compounds of the invention were synthesized fromthe corresponding amino ketone a as shown in Scheme 1, below.

Dimethylaminomethyl cyclohexanone a was condensed with aryl Grignardreagents b-d to give racemic amino alcohols. The racemic products werepurified by chiral chromatography on a semi-preparative chiralpak ADcolumn to give enantiomers 1, 24 and 28, and 2, 26 and 27. In additionto the values of R^(y) and R^(x) disclosed in Scheme 1, R^(y) and R^(x)are members independently selected from substituted or unsubstitutedalkyl, Cl, Br, F, NR¹⁰R¹¹, OR⁹, SR⁹ and substituted or unsubstitutedaryl.

Referring to Scheme 2, the parent primary amine for 2, compound 9, wasobtained via chiral HPLC separation of racemiccis-2-(aminomethyl)-1-(3,4-dichlorphenyl)cyclohexanol into consititutiveisomers 8 (faster moving enantiomer) and 9 (slower moving enantiomer). 9was converted to 2 via reductive animation with formic acid,formaldehyde and sodium cyanoborohydride. 2 was also obtained as theslower moving enantiomer after chiral HPLC separation of racemiccis-1-(3,4-dichlorophenyl)-2-((dimethylamino)methyl)cyclohexanol;reduction of 2 in a two step procedure with DEAD and acidic EtOHprovided mono-methyl derivative 4.

D. Pharmaceutical Compositions

In an exemplary aspect, the invention provides a pharmaceuticalcomposition including a compound described herein or a pharmaceuticallyacceptable salt or solvate thereof, and at least one pharmaceuticallyacceptable carrier. In various embodiments, the compound is a cisisomer. In an exemplary embodiment, the compound has a structure whichis a member selected from Formulae (I) to (IX).

As described in detail below, the pharmaceutical compositions of thepresent invention may be specially formulated for administration insolid or liquid form, including those adapted for oral administration,e.g., tablets, drenches (aqueous or non-aqueous solutions orsuspensions), parenteral administration (including intravenous andintramuscular), or epidural injection as, for example, a sterilesolution or suspension, or sustained release formulation. Thepharmaceutical compositions of the present invention may also bespecifically formulated for administration transdermally.

The pharmaceutical compositions of the invention may be administeredorally, parenterally, subcutaneously, transdermally, nasally, or by analsuppository. The pharmaceutical compositions of the invention may alsobe administered using controlled delivery devices.

Formulations of the present invention include those suitable for oraland parenteral administration, particularly intramuscular, intravenousand subcutaneous administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated and the particular mode ofadministration. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will generallybe that amount of the compound which produces a therapeutic effect,without being toxic to the patient. Generally, out of one hundredpercent, this amount will range from about 1 percent to aboutninety-nine percent of active ingredient.

Exemplary unit dosage formulations are those containing an effectivedose, or an appropriate fraction thereof, of the active ingredient, or apharmaceutically acceptable salt thereof. The magnitude of aprophylactic or therapeutic dose typically varies with the nature andseverity of the condition to be treated and the route of administration.The dose, and perhaps the dose frequency, will also vary according tothe age, body weight and response of the individual patient. In general,the total daily dose (in single or divided doses) ranges from about 1 mgper day to about 7000 mg per day, preferably about 1 mg per day to about100 mg per day, and more preferably, from about 10 mg per day to about100 mg per day, and even more preferably from about 20 mg to about 100mg, to about 80 mg or to about 60 mg. In some embodiments, the totaldaily dose may range from about 50 mg to about 500 mg per day, andpreferably, about 100 mg to about 500 mg per day. It is furtherrecommended that children, patients over 65 years old, and those withimpaired renal or hepatic function, initially receive low doses and thatthe dosage be titrated based on individual responses and/or bloodlevels. It may be necessary to use dosages outside these ranges in somecases, as will be apparent to those in the art. Further, it is notedthat the clinician or treating physician knows how and when tointerrupt, adjust or terminate therapy in conjunction with individualpatient's response.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,liposomes, micelle forming agents, e.g., bile acids, and polymericcarriers, e.g., polyesters and polyanhydrides; and a compound of thepresent invention. In certain embodiments, an aforementioned formulationrenders orally bioavailable a compound of the present invention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, caplets, lozenges (usinga flavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in- water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia), each containing a predeterminedamount of a compound of the present invention as an active ingredient. Acompound of the present invention may also be administered as a bolus,electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, caplets, pills, dragees, powders, granules and thelike), the active ingredient is mixed with one or more pharmaceuticallyacceptable carriers, such as sodium citrate or dicalcium phosphate,and/or any of the following: (1) fillers or extenders, such as starches,lactose, sucrose, glucose, mannitol, sialic acid and/or silicic acid;(2) binders, such as, for example, carboxymethylcellulose, alginates,gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants,such as glycerol; (4) disintegrating agents, such, as agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol, glycerolmonostearate, and non-ionic surfactants; (8) absorbents, such as kaolinand bentonite clay; (9) lubricants, such a talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof; and (10) coloring agents. In the case of capsules,tablets and pills, the pharmaceutical compositions may also comprisebuffering agents. Solid compositions of a similar type may also beemployed as fillers in soft and hard-shelled gelatin capsules using suchexcipients as lactose or milk sugars, as well as high molecular weightpolyethylene glycols and the like.

A tablet may be made by compression or molding, optionally, with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may release the active ingredient(s) only, or preferentially,in a certain portion of the gastrointestinal tract, optionally, in adelayed manner. Examples of embedding compositions which can be usedinclude polymeric substances and waxes. The active ingredient can alsobe in micro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which maycontain, sugars, alcohols, antioxidants, buffers, bacteriostats, soluteswhich render the formulation isotonic with the blood of the intendedrecipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such, as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain, adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue. Pharmaceuticalcompositions or unit dosage forms of the present invention in the formof prolonged-action tablets may comprise compressed tablets formulatedto release the drug substance in a manner to provide medication over aperiod of time. There are a number of tablet types that includedelayed-action tablets in which the release of the drug substance isprevented for an interval of time after administration or until certainphysiological conditions exist. Repeat action tablets may be formed thatperiodically release a complete dose of the drug substance to thegastrointestinal fluids. Also, extended release tablets thatcontinuously release increments of the contained drug substance to thegastrointestinal fluids may be formed.

Compounds of the invention can be also administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809;3,398,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydroxypropylmethyl cellulose, other polymermatrices, gels, permeable membranes, osmotic systems, multilayercoatings, microparticles, liposomes, microspheres, or a combinationthereof to provide the desired release profile in varying proportions.Suitable controlled-release formulations known to those of ordinaryskill in the art, including those described herein, can be readilyselected for use with the compounds of this invention. The invention thus encompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced, dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release other amountsof drug to maintain this level of therapeutic or prophylactic effectover an extended period of time. In order to maintain this constantlevel of drug in the body, the drug must be released from the dosageform at a rate that will replace the amount of drug being metabolizedand excreted from the body. Controlled-release of an active ingredientcan be stimulated by various conditions including, but not limited to,pH, temperature, enzymes, water, or other physiological conditions orcompounds.

Compounds of the present invention may also be formulated astransdermal, topical, and mucosal dosage forms, which forms include, butare not limited to, ophthalmic solutions, sprays, aerosols, creams,lotions, ointments, gels, solutions, emulsions, suspensions, or otherforms known to one of skill in the art. See, e.g., Remington'sPharmaceutical Sciences, 16th and 18th eds., Mack Publishing, Easton Pa.(1980& 1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., earners and diluents) and other materialsthat can be used to provide transdermal, topical, and mucosal dosageforms encompassed by this invention are well known to those skilled inthe pharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied.

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue.

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99.5% ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The preparations of the present invention may be given orally andparenterally. They are of course given in forms suitable for eachadministration route. For example, they are administered in tablets orcapsule form, by injection, and by intravenous administration. In oneembodiment, oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrastemal injection and infusion.

The selected dosage level will depend upon, a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the duration ofthe treatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex, weight,condition, general health and prior medical history of the patient beingtreated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Generally, oral, intravenous,intracerebroventricular and subcutaneous doses of the compounds of thisinvention for a patient will range from about 0,005 mg per kilogram toabout 5 mg per kilogram of body weight per day. In an exemplaryembodiment the oral dose of a compound of the invention will range fromabout 10 mg to about 300 mg per day. In an exemplary embodiment, theoral dose of a compound of the invention will range from about 20 mg toabout 250 mg per day. In an exemplary embodiment, the oral dose of acompound of the invention will range from about 100 mg to about 300 mgper day. In an exemplary embodiment, the oral dose of a compound of theinvention will range from about 10 mg to about 100 mg per day. In anexemplary embodiment, the oral dose of a compound of the invention willrange from about 25 mg to about 50 mg per day. In an exemplaryembodiment, the oral dose of a compound of the invention will range fromabout 50 mg to about 200 mg per day. Each of the above-recited dosageranges may be formulated as a unit dosage formulation.

The terms “treatment” or “treating” is intended to encompass therapy,preventing relapse, and amelioration of acute symptoms. Note that“treating” refers to either or both of the amelioration of symptoms andthe resolution of the underlying condition. In many of the conditions ofthe invention, the administration of a compound or composition of theinvention may act not directly on the disease state, but rather on somepernicious symptom, and the improvement of that symptom leads to ageneral and desirable amelioration of the disease state. The compoundsof the invention can also be used to prevent a disease (prophylaxis).

The patient receiving this treatment is any animal in need, includingprimates, in particular humans, and other mammals such as equines,cattle, swine and sheep, as well as poultry and pets in general.

The compounds and pharmaceutical compositions of the invention can beadministered in conjunction with other pharmaceutical agents, forinstance antimicrobial agents, such as penicillins, cephalosporins,aminoglycosides and glycopeptides. Conjunctive therapy thus includessequential, simultaneous and separate administration of the activecompound in a way that the therapeutic effects of the first administeredagent have not entirely disappeared when the subsequent agent isadministered.

In an exemplary embodiment, the subject exhibiting an indication forwhich a compound of the invention is therapeutically efficacious is nototherwise in need of treatment with a compound of the invention or acompound falling within the structural genus encompassing the compoundsof the invention.

IV. Methods A. Binding To Monoamine Transporter

In various aspects the invention provides a method of binding a compoundof the invention to a monoamine transporter. The method includescontacting the monoamine transporter and a compound of the invention.

The invention further provides a method of inhibiting binding of amonoamine transporter ligand to a monoamine transporter (such asserotonin transporter, dopamine transporter and norepinephrinetransporter). The method includes contacting the monoamine transporterand a compound of the invention. In an exemplary embodiment themonoamine transporter ligand is an endogenous monoamine, such asserotonin, dopamine or norepinephrine. In another exemplary embodiment,the ligand is a drug molecule or another small molecule known to havebinding affinity to a monoamine transporter. In another exemplaryembodiment, the monoamine transporter ligand is a radioactively labeledcompound, known to bind to the monoamine transporter.

In an exemplary embodiment, inhibition of ligand binding is shown usingan ex vivo binding assay, such as those described herein. In anexemplary embodiment, the compound of the invention inhibits meanbinding by between about 1% and about 100%, preferably by between about10% and about 100%, more preferably by between about 20% and about 90%when compared to vehicle. Inhibition of mean binding is preferably dosedependent.

B. Inhibition of Monoamine Transporter Activity

In various embodiments, the invention provides a method of modulating(e.g., inhibiting, augmenting) the activity of at least one monoaminetransporter, such as serotonin transporter, dopamine transporter andnorepinephrine transporter. The method includes contacting the monoaminetransporter and a compound of the invention. In an exemplary embodiment,the monoamine transporter is contacted with a compound of the inventionby administering to a subject a therapeutically effective amount of thecompound of the invention, or a pharmaceutically acceptable salt orsolvate thereof. The subject can be a human. In an exemplary embodiment,the monoamine transporter is dopamine transporter (DAT), serotonintransporter (SERT) or norepinephrine transporter (NET). In variousexemplary embodiments, the compound of the invention inhibits theactivity of at least two different monoamine transporters. Inhibition ofmonoamine transporter activity may be measured using assays known in theart. Exemplary assay formats include in vitro functional uptake assays.In an exemplary embodiment, the functional uptake assay utilizes anappropriate cell-line expressing a desired monoamine transporter. Invarious exemplary embodiments, the functional uptake assay utilizessynaptosomes isolated from brain tissue of an appropriate organism.Alternatively, inhibition of monoamine transporter activity may beassessed using receptor binding experiments known in the art, e.g.,utilizing appropriate membrane preparations. An exemplary assay involvestreatment of a test subject (e.g., a rat) with a compound of theinvention as well as a reference compound, followed by isolation ofbrain tissue and ex vivo analysis of receptor occupancy, as describedherein.

C. Inhibition of Monoamine Uptake

In various aspects, the invention provides a method of inhibiting uptakeof at least one monoamine (e.g., dopamine, serotonin, norepinephrine) bya cell. The method includes contacting the cell with a compound of theinvention. In an exemplary embodiment, the cell is a brain cell, such asa neuron or a glial cell. In one example, inhibition of monoamine uptakeoccurs in vivo. In an organism, neuronal uptake (also termed reuptake)of a monoamine such as dopamine or serotonin occurs, for example, fromthe synaptic cleft. Thus, in one embodiment, the neuronal cell is incontact with a synaptic cleft of a mammal. In another exemplaryembodiment, inhibition of monoamine uptake occurs in vitro. In thosemethods the cell, may be a brain cell, such as a neuronal cell or acell-type, which expresses a recombinant monoamine transporter.

In one embodiment, the compound inhibits uptake of at least twodifferent monoamines. This can, for example, be shown by performingvarious in vitro functional uptake assays utilizing a cell-type, whichsimultaneously expresses multiple different monoamine transporters (suchas isolated synaptosomes), or may be shown by using two different celltypes, each expressing a different monoamine transporter, such as arecombinant dopamine transporter, together with an appropriate, labeledmonoamine. Inhibition of monoamine uptake is demonstrated when theinhibitor (e.g., a compound of the invention) has an IC₅₀ of betweenabout 0.1 nM and about 10 μM, preferably between about 1 nM and about 1μM, more preferably between about 1 nM and about 500 nM, and even morepreferably between, about 1 nM and about 100 nM in a functionalmonoamine uptake assay, such as those described herein below.

D. Treatment of Neurological Disorders

In another aspect, the invention provides a method of treating aneurological disorder by inhibiting the activity at least one monoaminetransporter. The method includes administering to a subject in needthereof a therapeutically effective amount of a composition or compoundof the invention, or a pharmaceutically acceptable salt or solvatethereof. In an exemplary embodiment, the mammalian subject is a human.In another exemplary embodiment, the compound of the invention inhibitsthe activity of at least two different monoamine transporters. Forexample, the compound of the invention inhibits the activity of at leasttwo of serotonin transporter, dopamine transporter and norepinephrinetransporter. Inhibition of monoamine transporter activity may be shownby functional monoamine uptake assays as described herein below.

Demonstration of compound activity can be performed in variousart-recognized animal models. For example, anti-depressant activity of acompound of the invention may be shown by utilizing an appropriateanimal model of depression, such as the Rat Forced Swim Test, the MouseTail Suspension Test and Rat Locomotor Activity Analyses. The Rat ForcedSwim Test is also suitable for the analysis of compounds havingactivities against more than one monoamine transporter (mixed monoaminetransporter activity). For example, an increase in swimming activity isindicative of serotonin reuptake inhibition, while an increase inclimbing activity is indicative of norepinephrine reuptake inhibition.

In an various embodiments, the compounds of the invention are active inat least one animal model, which can be used to measure the activity ofthe compounds and estimate their efficacy in treating a neuroligaldisorder. For example, when the animal model is for depression (e.g.,mean immobility), the compounds of the invention are active when theyinhibit mean immobility by between about 5% and about 90%, preferablybetween about 10% and about 70 % more preferably between about 1.0% andabout 50%, more preferably between about 15% and about 50% in at leastone animal model, when compared to vehicle. In various embodiments, thecompounds of the invention produce a similar disparity in measuredendpoint between treated animals and animals administered vehicle.

In various embodiments, the invention provides a method of effecting ananti-depressant-like effect. The method includes administering to amammalian subject in need thereof a therapeutically effective amount ofa compound or composition of the invention, or a pharmaceuticallyacceptable salt or solvate thereof. Anti-depressant-like effects may bemeasured using an animal model of disease, such as those describedherein.

In various exemplary embodiments, the neurological disorder is a memberselected from the group consisting of depression (e.g., major depressivedisorder, bipolar disorder, unipolar disorder, dysthymia and seasonalaffective disorder), cognitive deficits, fibromyalgia, pain (e.g.,neuropathic pain), sleep related disorders (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders, which areproduced by psychiatric conditions, chronic fatigue syndrome, attentiondeficit disorder (ADD), attention deficit hyperactivity disorder (ADHD),restless leg syndrome, schizophrenia, anxieties (e.g. general anxietydisorder, social anxiety disorder, panic disorder), obsessive compulsivedisorder, posttraumatic stress disorder, seasonal affective disorder(SAD), premenstrual dysphoria, post-menopausal vasomotor symptoms (e.g.,hot flashes, night sweats), and neurodegenerative disease (e.g.,Parkinson's disease, Alzheimer's disease and amyotrophic lateralsclerosis), manic conditions, dysthymic disorder, cyclothymic disorder,obesity and substance abuse or dependency (e.g. cocaine addiction,nicotine addiction). In an exemplary embodiment, the neurologicaldisorder is depression, such as major depressive disorder. In anexemplary embodiment, the compounds of the invention are useful to treattwo conditions/disorders, which are comorbid, such as cognitive deficitand depression.

Neurological disorder includes cerebral function disorders, includingwithout limitation, senile dementia, Alzheimer's type dementia,cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorders, Lennox syndrome, autism, and hyperkinetic syndrome.

Neuropathic pain includes without limitation post herpetic (orpost-shingles) neuralgia, reflex sypathetic dystrophy/causalgia or nervetrauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated using themethods of the invention include obesity: migraine or migraine headache;urinary incontinence, including without limitation involuntary voidingof urine, dribbling or leakage of urine, stress urinary incontinence(SUI), urge incontinence, urinary exertional incontinence, reflexincontinence, passive incontinence, and overflow incontinence: as wellas sexual dysfunction, in men or women, including without limitationsexual dysfunction caused by psychological and/or physiological factors,erectile dysfunction, premature ejaculation, vaginal dryness, lack ofsexual excitement, inability to obtain orgasm, and psycho-sexualdysfunction, including without limitation, inhibited sexual desire,inhibited sexual excitement, inhibited female orgasm, inhibited maleorgasm, functional, dyspareunia, functional vaginismus, and atypicalpsychosexual dysfunction.

In an exemplary embodiment, the neurological disorder is obesity, andthe therapeutically effective amount of compound to supply to a patientis enough so that said patient feels satiated.

In an exemplary embodiment, the compounds described herein treat/preventa central nervous disorder, without causing addiction to said compounds.

The following examples are provided to illustrate the exemplary featuresof the invention.

EXAMPLES

The following examples are provided to illustrate selected embodimentsof the invention and are not to be construed as limiting its scope.

Example 1 1a. General Procedures

In the examples, below, the following general experimental procedureswere used unless otherwise noted: All commercial reagents were usedwithout further purification. Anhydrous reactions were performed inflame-dried glassware under N₂. NMR spectra ware recorded on a Varian400 MHz spectrometer in deutcrochloroform or methanol-d⁴ withtrimethylsilane (TMS) as an internal reference. Silica gel columnchromatography was performed using an ISCO Combiflash system withdetection at 254 nm or using ISCO normal phase silica gel cartridges.

1b. Analytical HPLC

Analytical HPLC was performed on a Hewlett Packard Series 1100 pumpconnected to an Agilent Zorbax RX-C18 5 μm, 4.6×250 mm column, withdetection on a Hewlett Packard Series 1100 UV/Vis detector monitoring at214 and 254 nm. Typical flow rate=1 ml/min. Three different HPLC columnsand various elution protocols were used. For example, (1) Agilent ZorbaxRX-C18 5 μm, 4.6×250 mm column running a linear gradient. Solvent A=H2Ow/0.05% TFA, Solvent B=MeCN w/0.05% TFA. Time 0 min=5% Solvent B, time 4min=40% Solvent B, time 8 min=100% Solvent B, 12 min=5% Solvent B, 20min=5% Solvent B; (2) Phenomenex 3μ C18 column running a 3 minutegradient of 5→100% B (acetonitrile/0.1% formic acid) and Solvent A(water/0.1% formic acid); (3) Phenomenex 5μ C18 column running a 5minute gradient of 5→100% B where solvent B (acetonitrile/0.1% formicacid) and solvent A (water/0.1% formic acid).

1c. Reverse Phase HPLC Purification

Reverse phase HPLC purification was performed on a Gilson system using aPhenomenex 5μ C18 (5×21.2 mm) column. The standard separation methodwas: 10 minute gradient of 10→100% B (acetonitrile/0.1% formic acid) insolvent A (water/0.1% formic acid). Crude samples were typicallydissolved in MeOH. Fractions were concentrated by Genovac(centrifugation at low pressure).

1d. GC-MS

Gas chromotography was performed on a Hewlett Packard 6890 Series GCSystem with an HPI column (30 meters, 0.15μ film thickness) coupled to aHewlett Packard 5973 Series Mass Selective Detector. The followinglinear temperature gradient was used: 100° C. for 5 minutes, then 20°C./min to 320° C. Hold @320° C. for 10 minutes.

1e. LCMS

LCMS was performed on an Agilent 1100 Series system connected to aMicromass Platform LC. The following column and gradient was used:Column: Luna C18(2), 3 um particle size 30×2.0 mm column dimension. Flowrate=0.5 mL/min, Solvent A=0.1 M NH₄Ac in 95% H₂O, 5% MeOH, pH 6.0,Solvent B=Solvent B: 0.1 M NH₄Ac in MeOH. Linear gradient with 6entries: Time 0 min=100% Solvent A, time 10 min=100% Solvent B, time 12min=100% Solvent B, time 12 min 10 sec=100% Solvent A, time 14 min=100%Solvent A, time 14 min 20 sec=100% Solvent A.

1f. Microwave (μW) Recrystallization

The crude salt (e.g., HCl salt) was loaded into a microwave vessel witha stir bar. The recrystallization solvent was added and the vessel washeated at the target temperature for a given time. The vessel was cooledto 50° C. in the reactor, was then removed and allowed to slowly cool toRT. N,N-dimethyl amines were typically recrystallized in EtOAc orEtOAc:CH₃CN (2:1). N-Me or primary amines were typically recrysallizedin CH₃CN.

Example 2 2a. Experimental Procedures and Characterization Data

To a solution of ketone a (2.0 g, 13 mmol) in THF (20 mL) at −78° C. wasadded 3,4-dichlorophenylmagnisium bromide (0.5 M in THF, 38 mL, 19mmol). The reaction mixture was stirred for 30 min at −78° C. beforebeing warmed to 0° C. over 30 min. A saturated solution of NH₄Cl (30 mL)was added to the reaction mixture to quench the reaction. The resultingproduct was extracted with diethyl ether (2×100 mL). The combinedextracts were dried and concentrated. The residue was subjected tosilica gel column chromatography (ethyl acetate/hexane/Et₃N=1:10:0.1) togive the racemic mixture of 1 and 2 (3.5 g, 90%). The racemic mixturewas separated by chiral AD column (hexane/iPrOH/DEA=95/5/0.1 as eluent)to give pure 1 (Faster moving enantiomer) and 2 (Slower movingenantiomer).

2a1. Data for 1/2

¹H NMR (440 MHz, CD3OD) δ7.73; (d, J=1.6 Hz, 1H), 7.52; (d, J=8.4 Hz,1H), 7.47; (dd, J=1.6, 8.4 Hz, 1H), 3.01; (dd, J=13.2, 10.4 Hz, 1H),2.76; (s, 3H), 2.65; (s, 3 H), 2.57; (dd, J=2.0, 13.2 Hz, 1H), 2.28; (m,2H), 1.9; (m, 2H), 1.70; (m, 2H), 1.6; (m, 2H); ¹³C NMR (100 MHz, CD₃OD)δ148.86, 132.32, 130.32, 127.49, 125.08, 74.11, 60.22, 45.03, 41.22,40.29, 25.71, 24.64, 21.16; ESI MS m/z 302.1, 304.0.

2b. Dealkylation of Cycloalkylamines

To a solution of 2 (0.8 g, 2,65 mmol) in toluene was added DEAD (0.69 g,0.63 mL, 3.96 mmol). The reaction mixture was heated at 100° C. for 4 hbefore being concentrated. The residue was dissolved in 30 mL of EtOHand a saturated solution of NH₄Cl (30 mL) was added. The reactionmixture was stirred at 50 for 6 h before being concentrated, NaOHsolution (2 M, 10 mL) was added to the resulting mixture and the productwas extracted with diethyl ether (2×80 mL). The combined extracts weredried and concentrated. The residue was purified by reserve phase columnchromatography (CH₃CN/H₂O=5/95 to 95/5) to give 4 (0.32 g, 42%).

2b1. Data for 4

¹H NMR (400 MHz, CD3OD) δ7.60; (s, 1H), 7.37; (m, 2H), 2.57; (dd, J=2.0,12.4 Hz, 1H), 2.28; (dd, J=2.8, 12.4 Hz, 1H), 2.23; (s, 3H), 1.88; (m,2H), 1.78; (m, 2H), 1.62; (m, 1H), 1.56; (m, 2H), 1.40; (m, 1H); ¹³C NMR(100 MHz, CD₃OD) δ150.86, 132.40, 130.21, 130.09, 127.56, 124.77, 77.03,53.54, 43.95, 40.82, 36.81, 26.45, 26.05, 22.05; ESI MS m/z 288.1.

2c. Synthesis of Cyclohexylamines from Cyclohexanone

To a solution of cyclohexanone (23.7 g, 25.0 mL, 0.242 mol) in H₂O (50mL) was added HCHO (37%, 37.5 mL, 0.46 mol) and K₂CO₃ (0.52 g, 3.76mmol). The reaction mixture was stirred for three hours at 60° C. Thenthe product was extracted with diethyl ether (2×300 mL). The combinedextracts were dried and concentrated. The residue was purified by silicagel column chromatography (ethyl acetate/hexane=1.7 to 1:2) to give k(10.8 g, 35%).

To a solution of k (3.2 g, 25 mmol) in THF (60 mL) at −20° C. was added3,4-dichlorophenylmagnisium bromide solution (0.5 M, 100 mL, 50 mmol).The reaction mixture was stirred for 30 min before being quenched byNH₄Cl solution (20 mL). The product was then extracted by diethyl ether(2×100 mL). The combined extracts were dried and concentrated. Theresidue was purified by silica gel column chromatography (hexane/ethylacetate=1:7 to 1:2) to give m (2.1 g, 31%).

To a solution of m (1.6 g, 5.8 mmol) in THF (40 mL) at r.t. was addedPPh₃ (1.8 g, 7.0 mmol), DEAD (1.2 g, 7.0 mmol) anddiphenylphosphorazidate (DPPA) (1.9 g, 7.0 mmol). The resulting yellowsolution was stirred overnight before being concentrated. The residuewas subjected to silica gel column chromatography (hexane/ethylacetate)=1:10 to 1:1 to give the desired product n (1.32 g, 74%).

To a solution of n (1.00 g, 3.34 mmol) in THF (30 mL) was added PPh₃(1.75 g, 6.68 mmol). The reaction mixture was stirred for 24 h beforeH₂O (10 mL was added. The resulting mixture was stirred for another 2days before being concentrated. The residue was subjected to reversephase column chromatography (CH₃CN/H₂O=5/95 to 95/5) to give the desiredproduct o (0.75 g, 82%). The racemic mixture was separated by chiral ADcolumn with (ethanol/methanol/hexane/DEA=3/2/95/0.1) to give the pureenantiomer 8 (Faster moving enantiomer) and 9 (Slower movingenantiomer).

2e1. Data for 8/9

¹H NMR (400 MHz, CD3OD) δ7.73; (broad, 1H), 7.40; (d, J=8.4 Hz, 1H),7.30; (m, 2H), 2.69; (dd, J=2.0, 13.2 Hz, 1H), 2.56; (dd, J=2.8, 13.2Hz, 1H), 2.20; (m, 2H), 1.80; (m, 2H), 2.28; (m, 2H), 1.60; (m, 2H),1.50 (m, 3H); ¹³C NMR (100 MHz, CD₃OD) δ150.75, 132.38, 130.19, 130.06,127.64, 124.81, 77.28, 43.63, 43.45, 41.16, 26.38, 25.34, 22.06; ESI MSm/z 274.1, 276.0.

Compound 9 was converted to 2 via reductive amination with formaldehyde.

Example 3 3a. Experimental Procedures

Experimental conditions utilized for these syntheses were similarly tothose employed in Examples 1 and 2.

Experimental conditions utilized for these syntheses were similar tothose employed in Examples 1 and 2.

Example 4 4a. In Vitro Human 5-HT/NE/DA Reuptake Inhibition Data

Compounds were tested for their inhibition of functional uptake ofserotonin (5-HT), norepinephrine (NE), and dopamine (DA), insynaptosomes prepared from rat whole brain, hypothalamus, or corpusstraiatum, respectively, and/or using recombinant human transporters.Details of the assays are described in US 2007/0203111 A1, which isincorporated by reference. Results for functional uptake assay for humanreuptake transporters are shown below.

Corporate ID 5-HT IC₅₀ (nM) NE IC₅₀ (nM) DA IC₅₀ (nM) 2 +++ * # 4 ++++ *# 9 ++++ *** # 1 + ** ## 8 +++ **** ## 5-HT IC50 NE IC50 DA IC50 1-2000nM (+) 10-200 nM (*) 10-200 nM (#) 2001-7000 nM (++) 201-1000 nM (**)201-1000 nM (##) 7001-10000 nM (+++) 1001-5000 nM (***) 1001-5000 nM(###) >10001 nM (++++) >5001 nM (****) 5001-10000 nM (####)

4b. In Vitro PK Data (Human Metabolic Stability, Inhibition of CYP450Enzymes, Inhibition of HERG Current)

CYP inhibition IC₅₀ Corporate HLM t_(1/2) HERG IC₅₀ (microM) 5 isoforms(2D6, ID (min) (microM) 2C9, 3A4, 2C19, 1a) 2 + ** ## 4 ++ * # 1 + — —HLM t½ HERG IC50 CYPI IC50 25-175 min (+) 1-15 μM (*) >10 μM (#) 176-325min (++) 16-30 μM (**) >20 μM (##)

4c. Tail Suspension Test, Locomotor Activity Test and Forced Swim Test4c1. Mouse Tail Suspension Test

The method, which detects antidepressant activity, follows thatdescribed by Stéru et al (Psychopharmacology, 85: 367-370 (1985)).Rodents, suspended by the tail, rapidly become immobile. Antidepressantsdecrease the duration of immobility.

The behavior of the animal was recorded automatically for 5 minutesusing a computerized device (Med-Associates Inc.) similar to thatdeveloped by Stéru et al (Prog. Neuropsychopharmacol. Exp. Psychiatry11: 659-671 (1987)). Ten to twelved mice were tested in each group.Compounds were typically evaluated at 3 doses (1-30 mg/kg), administeredorally one time: 30-60 minutes before the test, and compared with avehicle control group. Desipramine (100 mg/kg), administered under thesame experimental conditions, was used as the positive referencesubstance.

Data were analyzed by one way analysis of variance (ANOVA) followed bypose-hoc comparisons where appropriate. An effect was consideredsignificant if p>0.05. Data are represented as the mean and standarderror to the mean (s.e.m).

4c2. Locomotor Activity

In order to ensure effects of the compounds on immobility time were notrelated to a general stimulant effect on baseline motor activity,locomotor activity was assessed using photocell monitored cages(Med-Associates Inc.). Each test chamber was equipped with infraredphotocell beams to measure movements of the animals. Horizontal andvertical activity were measured.

Rats or mice were pretreated with vehicle or test compounds and placedback in home cage, following which they were individually placed inlocomotor cages and activity was monitored in 1-5 minute intervals forintervals up to 60 min.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriate. An effect was consideredsignificant if p>0.05. Data are represented as the mean and standarderror to the mean (s.e.m).

4c3. Result Summary

Effects of compounds of the invention were evaluated in the mouse trailsuspension and locomotor activity test. Results showed that allcompounds tested exhibited an antidepressant-like profile (i.e.,significantly decreased immobility time) with MED's in the range of 3-30mg/kg, PO. At doses active in the tail suspension test, no change or adecrease in baseline motor activity was observed indicating thatantidepressant-like activity was not due to a general stimulant effect.

Effects of compounds of the invention were also evaluated in the ratforced swim and locomotor activity tests. All compound exhibitedantidepressant-like effects with MED's in the range of 10-30 mg/kg, PO.The decrease in immobility produced by these compounds appeared to bedue to increases in swimming and climbing behaviors indicative of mixedtransporter activity (i.e., SNRI profiles). Similar to the mouse tailsuspension results, the rat forced swim test also showed anti-depressantlike activity for this compound.

Mouse Tail Suspension and Locomotor Activity Results

Treatment Dose Mouse Tail Suspension (mg/kg, Mean Immobility MouseLocomotor Activity PO) Time ± S.E.M. Total Distance Traveled ± S.E.M. 20 +++ *** 0.3 +++ ** 1 +++ ** 3 + *** 2 0 ++++ ** 3 +++ ** 10 + ****30 + * 4 1 ++++ ** 3 ++++ ** 10 +++ *** 30 + * Mouse Tail SuspensionMouse Locomotor Activity 100-160 (+) 100-500 (*) 161-170 (++) 501-700(**) 171-190 (+++) 701-900 (***) >191 (++++) >901 (****)

After the TST, brain and plasma samples were collected from 4representative mice from each treatment group for analysis of 2 and 4exposure levels in these tissues. 2 exhibited a does-dependent decreasein immobility in this test (see above). Significant levels of the 4metabolite were found in plasma and brain levels subsequent to oral 2administration.

4c4. Rat Forced Swim Test

The method, which detects antidepressant activity, followed thatdescribed by Porsolt et al (Eur. J. Pharmacol., 47: 379-391 (1978)) andmodified by Lucki et al. (Psychopharm. 121: 66-72 (1995)). Rats forcedto swim in a situation from which they cannot escape rapidly becomeimmobile. Antidepressants decrease the duration of immobility. Inaddition, distinct patterns of active behaviors are produced byantidepressants that selectively inhibit norepinephrine (NE) andserotonin (5-HT) uptake in this test. Selective NE reuptake inhibitorsdecrease immobility by increasing climbing behaviors whereas selective5-HT reuptake inhibitors decrease immobility by increasing swimmingbehaviors.

Rats were individually placed in a cylinder (Height=40 cm; Diameter=20cm) containing 22 cm water (25° C.) for 15 minutes on the first day ofthe experiment (Session 1) and were then put back in the water 24 hourslater for a 5 minute test (Session 2). The sessions were videotaped andduration of immobility as well as swimming and climbing behaviors duringthe 5 minute test were measured. Twelve rats were tested in each group.The test was performed blind. Compounds were typically evaluated at 3doses (1-30 mg/kg), administered orally 2 times: 24 hours and 30-60minutes before the test (Session 2), and compared with a vehicle controlgroup. Desipramine (20 mg/kg i.p.), administered under the sameexperimental conditions, was used as the positive reference substance.

Data were analyzed by one way analysis of variance (ANOVA) followed bypost-hoc comparisons where appropriated. An effect will be consideredsignificant if p>0.05. Data are represented as the mean and standarderror to the mean (s.e.m.).

Rat Forced Swim and Locomotor Activity Results

Rat Locomotor Treatment Rat Forced Swim Activity Dose (Means ± S.E.M.)Total Distance (mg/kg, PO) Immobility Swimming Climbing Traveled ±S.E.M. 2 0 +++ * # ∘ 1 +++ * ## ∘ 3 +++ * # ∘ 10 + ** ### ∘∘∘ ImmobilitySwimming Climbing Total Distance Traveled 1-20 (+) 1-5 (*) 1-10 (#)100-2500 (∘) 21-40 (++) 6-9 (**) 11-20 (##) 2501-5000 (∘∘) >41 (+++) >10(***) >21 (###) >5001 (∘∘∘)

Example 5 5a. Ex Vivo Binding Assay

Receptor occupancy of central noradrenaline (NA), 5-HT and dopamine (DA)transporter sites following peripheral administration of compounds wasdetermined using [³H] nisoxetine, [³H] citalopram and [³H] WIN 35428binding, respectively. Liquid scintillation counting was used toquantify the radioactivity.

C57BL/6 mice (25-30 g) were dosed orally with either vehicle or compoundat 4 dose level. Mice were sacrificed 60 minutes after treatment. Wholebrains were removed and cortex and striata dissected out before beingfrozen on dry ice. The brain tissue was stored at −20° C. until the dayof the assay. The cortex from each hemisphere was frozen separately. Onewas used to determine occupancy of NA transporter sites and the otheroccupancy of 5-HT transporter sites. Striatum was used to determineoccupancy of DA transporter sites.

Frontal cortex from each hemisphere or striata was homogenizedindividually in ice-cold assay buffer using a tight fitting glass/Teflonhomogenizer and used immediately in the binding assay.

5b. [³H] Citalopram Binding to 5-HT Transporter (SERT) Sites in MouseBrain

Cortical membranes (400 μL; equivalents to 1.25 mg wet weight oftissue/tube) were incubated with 50 μL of [³H] citalopram at a singleconcentration of 1.3 nM and either 50 μl of buffer (total binding) or 50μl of paroxetine (0.5 μM; non-specific binding) for 1 h at 27° C. Foreach animal, three tubes were used for the determination of totalbinding and three tubes were used for the determination of non-specificbinding.

5c. [³H] Nisoxetine Binding to Norepinephrine Transporter (NET) Sites inMouse Brain

Cortical membranes (400 μL; equivalent to 6.0 mg wet weight oftissue/tube) were incubated with 50 μL of [3H] nisoxetine at a singleconcentration of 0.6 nM and either 50 μL of buffer (total binding) or 50μL of mazindol (1 μM; non-specific binding) for 4 h at 4° C. For eachanimal, three tubes were used for the determination of total binding andthree tubes were used for the determination of non-specific binding.

5d. [³H] WIN 35428 Binding to DA Transporter (DAT) Sites in Mouse Brain

Striatal membranes (200 μL; equivalent to 2 mg wet weight oftissue/tube) were incubated with 25 μL of [3H] WIN 35428 at a singleconcentration of 24 nM and either 25 μL, of buffer (total binding) or 25μL of GBR12935 (1 μM; non-specific binding) for 2 h at 4° C. For eachanimal, two tubes were used for the determination of total binding andtwo tubes for the determination of non-specific binding.

Membrane bound radioactivity was recovered by filtration under vacuumthrough Skatron 11731 filters, presoaked in 0.5% PEI, using a Skatroncell harvester. Filters were rapidly washed with ice-cold phosphatebuffer and radioactivity (dpm) was determined by liquid scintillationcounting (1 mL Packard MV Gold scintillator).

5e. Data Analysis

A value for specific binding (dpm) was generated by the subtraction ofmean non-specific binding (dpm) from mean total binding (dpm) for eachanimal. Data are presented as mean specific binding (dpm) and as apercentage of the vehicle-treated control taken as 100%.

5f. Results Summary

Ex vivo SERT, NET and DAT binding/receptor occupancy data were generatedfor 2.

Ex Vivo Biding Profile of 2 in Mice

Treatment Mean Specific Binding (dpm) ± S.E.M. Dose, (Values in BracketsDenote % Transporter Occupancy) (mg/kg PO) NET SERT DAT 2 0 1050 ± 343302 ± 111 43327 ± 4273 1 845 ± 44 (19)* 2926 ± 119 (11) 36886 ± 1873(15)  3 583 ± 20 (44)* 3330 ± 176 (−1) 21744 ± 1050 (50)* 10 271 ± 12(74)* 3104 ± 131 (6)   8941 ± 305 (79)* 30 115 ± 13 (89)* 3126 ± 204(5)   4236 ± 538 (90)*

Example 6 Summary of Selected In Vitro Data for Test Compounds

5-HT NE DA IC50 nM IC50 nM IC50 nM  1 + ** ##  2 + * #  4 ++++ * #  7 ++** #  8 +++ **** ##  9 ++++ *** # 10 ++ ** # 11 + ** # 12 A/B +++ ****### 13 A/B n.t n.t. n.t. 14 A/B ++ **** ## 15 A/B ++ **** ## 16 A/B +**** # 17 A/B ++ **** ## 18 A/B +++ *** # 19 A/B n.t n.t. n.t. 20 A/Bn.t n.t. n.t. 21 A/B + **** # 22 A/B n.t n.t. n.t. 23 A/B ++ **** ## 24+++ **** #### 25 ++++ * # 26 + *** #### 27 ++ * ## 5-HT IC50 NE IC50 DAIC50 1-2000 nM (+) 10-200 nM (*) 10-200 nM (#) 2001-7000 nM (++)201-1000 nM (**) 201-1000 nM (##) 7001-10000 nM (+++) 1001-5000 nM (***)1001-5000 nM (###) >10001 nM (++++) >5001 nM (****) 5001-10000 nM (####)Human Liver Microsome = HLM; Rat Liver Microsome = RLM; Mouse LiverMicrosome = MLM.

Example 7 7a. Resperine Rat Model

The effects of compound 4 alone and in combination with L-DOPA wereevaluated in the resperine-treated rat Parkinson's disease model. Themethod, which detects antiparkinson activity (reveral of motor deficitsand akinesia), follows that described by Johnson et al. (Exp. Neurol.191, 243-250, 2005). Eighteen hours prior to behavioural testing, ratswere lightly anaesthetized with isoflurane and reserpine (3 mg/kg, sc)was injected along with saline (50 ml/kg) to prevent dehydration.

7b. Behavioral Assessment

Accelerating Rotarod: Performance on an accelerating rotarod wasassessed using a 4-station rat rotarod (MedAssociates, USA). The speedof rotation of the rotarod was increased from 3.5 to 35 rpm over 5minutes and the time for which the animal remained on the rod determinedas the mean of three trials.

Catalepsy Test: Catalepsy was assessed by placing the rat's forepaws ontop of a horizontal wooden rod suspended 6 cm above the bench surface.Time taken to remove both paws from the rod was recorded, up to amaximum of 120 seconds. Three trials per animal were conducted.

Open Field: Activity in an open field arena was assessed using automatedactivity monitors (Linton Instrumentation, UK). Rats were placed in theactivity boxes and locomotor activity was recorded over a 240 minuteperiod.

Drug Administration: For the monotherapy experiment, the effects of 5different treatments were assessed: 1) vehicle (sterile water, PO), 2) 3mg/kg compound 4 (PO), 3) 10 mg/kg compound 4 (PO), 4) 30 mg/kg compound4 and 5) 80 mg/kg (IP) of the positive reference substance, L-DOPA (80mg/kg). In the combination experiment, 5 different treatments wereassessed: 1) compound 4 vehicle (PO)+L-DOPA vehicle (IP), 2) compound 4(10 mg/kg, PO)+L-DOPA vehicle (IP), 3) compound 4 vehicle (PO)+L-DOPA(30 mg/kg, IP), 4) compound 4 (10 mg/kg, PO)+L-DOPA (30 mg/kg, IP) and5) compound 4 vehicle (PO)+L-DOPA (80 mg/kg, IP). Treatments were givenin a randomized fashion and each animal received all treatmentconditions. Compound 4 was administered 60 minutes prior to behavioralassessment and L-DOPA was administered immediately prior to behavioraltesting.

Results showed that compound 4 (3-30 mg/kg, PO) alone dose-dependentlyimproved performance in a variety of behavioral tests (baselinelocomotor activity, FIG. 2, rotarod, FIG. 3, and catalepsy, FIG. 4).Depending upon the behavioral test, effects of compound 4 were similaror smaller than those observed with L-DOPA (80 mg/kg). In thecombination experiment, the combination of compound 4 (10 mg/kg, PO) andlow dose L-DOPA (30 mg/kg) showed effects that were equal in magnitudeand of longer duration than those provided by a higher dose of L-DOPAdoes (80 mg/kg). FIG. 5.

The data suggest that compound 4 may have some anti-parkinsonian actionsas monotherapy although effects are not as powerful as L-DOPA. Thecombination compound 4 and low does L-DOPA experiments indicatedanti-parkinsonian actions that were equal in magnitude and of longerduration than those provided by a higher L-DOPA dose. Compound, 4 couldthus be described as “L-DOPA sparing”.

Example 8 8a. Rat Unilateral 6-hydroxydopamine (6-OHDA) Lesion Model

The effects of compound 4 alone and in combination with L-DOPA wereevaluated in the rodent 6-OHDA-lesioned rat Parkinson's disease model.The method, which detects antiparkinson activity (reveral of motordeficits and akinesia), follows that described by Henry et al. (ExpNeurol, 151(2):334-42, 1998).

Animal Preparation: Prior to surgery, rats were administered pargyline(5 mg/kg, ip) and desipramine (25 mg/kg ip) to optimize subsequent6-OHDA availability and increase specificity for toxicity todopaminergic neurons. Rats were then anesthetized with isoflurane andplaced in a stereotaxic frame. After exposure of Bregma, a burr hole wasdrilled in the skull above the right median forebrain bundle atco-ordinates: 2.8 mm posterior and 2 mm lateral to Bregma (according tothe atlas of Paxinos and Watson, 1986). A 28G Hamilton needle was thenlowered 9 mm below the skull. Injection of 6-OHDA (12.5 μg in 2.5 μl)was then made (1 μl/min). The needle was then left in place for 4minutes to ensure complete absorption of the solution. After slowretraction of the injection needle, the wound was closed and animalswere administered saline (50 ml/kg, sc), an analgesic (Ketonprofen, 0.5mg/kg) and a broad spectrum antibiotic (enrofloxacin, 75 mg/kg).Following surgery, animals were left untreated for 3 weeks to allow thelesion to develop and stabilize prior to the start of behavioralassessment.

8b. Behavioral Assessment

Paw Placing Test: The paw placing test assesses correct placing of eachforepaw in response to a sensory stimulus. Rats were gently held bytheir torsos and each forepaw was restrained between thumb andforefinger whilst allowing the opposite paw to hang free. The rat wasthen held parallel to the edge of a table with the free forelimb placedadjacent to the edge. The animal was then moved towards the table andthe vibrissae brushed against the table edge to elicit a forelimbplacing response from the free limb. A total of ten trials wereconducted in quick succession before repeating the procedure for theother paw. The test was quantified as the percentage of successfulplacing responses of the limb contralateral to the side of the 6-OHDAlesion. Placement of the limb ipsilateral to the side of the lesion wassuccessful in 100% of cases in all animals.

Drug Administration: For the monotherapy experiment, the effects of 5different treatments were assessed: 1) vehicle (sterile water, PO), 2) 3mg/kg compound 4 (PO), 3) 10 mg/kg compound 4 (PO), 4) 30 mg/kg compound4 and 5) 6.5 mg/kg (IP) of the positive reference substance, L-DOPA. Inthe combination experiment, 5 different treatments were assessed: 1)compound 4 vehicle (PO)+L-DOPA vehicle (IP), 2) compound 4 (10 mg/kg,PO)+L-DOPA vehicle (IP), 3) compound 4 vehicle (PO)+L-DOPA (2 mg/kg,IP), 4) compound 4 (10 mg/kg, PO)+L-DOPA (2 mg/kg, IP) and 5) compound 4vehicle (PO)+L-DOPA (6.5 mg/kg, IP). Treatments were given in arandomized fashion and each animal received each treatment condition.Compound 4 was administered 60 minutes prior to behavioral assessmentand L-DOPA was administered immediately prior to behavioral testing.

Results showed that compound 4 (3-30 mg/kg, PO) alone produced little orno improvement in performance in the paw placement task. The combinationof compound 4 (10 mg/kg, PO) and low does L-DOPA significantly increasedpaw placement performance providing some evidence of synergy betweenactions of compound 4 and L-DOPA (FIG. 6).

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modification of the invention in addition to those shownand described herein will become apparent to those skilled in the artand are intended to fall within the scope of the appended claims.

All patents, patent applications, and other publications cited in thisapplication are incorporated by reference herein in their entirety forall purposes.

What is claimed is:
 1. A compound having a structure which is a memberselected from the group consisting of:

wherein n is an integer selected from the group consisting of 0 to 2; sis an integer selected from the group consisting of 0 to 2; A is amember selected from the group consisting of H, substituted orunsubstituted alkyl, halogen and substituted or unsubstituted haloalkyl;X is a member selected from the group consisting of H, halogen,substituted or unsubstituted alkyl, substituted or unsubstituted aryl,substituted or unsubstituted haloalkyl and OR⁵ wherein 'R⁵ is a memberselected from the group consisting of H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl substituted or unsubstituted heteroaryl, acyl andS(O)₂R^(5a), wherein R^(5a) is a member selected from the groupconsisting of substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl; Y and Z are members independently selected from thegroup consisting of halogen, CF₃, CN, OR⁹, SR⁹, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heterocycloalkyl, NR¹⁰R¹¹ andNO₂. wherein Y and Z, together with the atoms to which they areattached, are optionally joined to form a 5- to 7-membered ring,optionally including from 1 to 3 heteroatoms, wherein R⁹ is a memberselected from the group consisting of H, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted heterocylcoalkyl; and R¹⁰ and R¹¹ are membersindependently selected from the group consisting of H, OR¹², acyl,S(O)₂R¹³, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, wherein R¹² is a member selected from the groupconsisting of H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl; and R¹³ is a member selected from the group consistingof substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, wherein R¹⁰ and R¹¹, together with the atoms to whichthey are attached, are optionally joined to form a 3- to 7-memberedring, optionally including from 1 to 3 heteroatoms; R¹ and R² aremembers independently selected from the group consisting of H, halogen,CN, CF₃, OR⁶, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl, wherein R⁶ is a member selected from the groupconsisting of H, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl and substituted or unsubstitutedheterocycloalkyl; and R³ and R⁴ are members independently selected fromthe group consisting of H, OR⁷, acyl, S(O)₂R⁸ substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl, wherein R⁷is a member selected front the group consisting of H, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl; R⁸ is amember selected from the group consisting of substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl and substituted or unsubstituted heterocycloalkyl; andwherein at least two of R¹, R², R³ and R⁴, together with the atoms towhich they are attached, are optionally joined to form a 3- to7-membered ring, optionally including from 1 to 3 heteroatoms.
 2. Thecompound of claim 1, wherein R³ and R⁴ are members independentlyselected front the group consisting of substituted or unsubstitutedC₁-C₄ alkyl and substituted or unsubstituted C₁-C₄ heteroalkyl.
 3. Thecompound of claim 1, wherein R³ and R⁴ are members independentlyselected from the group consisting of substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl and substituted orunsubstituted cycloalkyl.
 4. The compound of claim 1, having a structurewhich is a member selected from the group consisting of:

wherein A is H.
 5. The compound of claim 4, having a structure which isa member selected from the group consisting of:


6. The compound of claim 4, wherein Y and X are members independentlyselected from the group consisting of H, halogen, CN and CF₃.
 7. Thecompound of claim 6, wherein Y and X are chloro.
 8. The compound ofclaim 7, wherein s is
 1. 9. The compound of claim 8, wherein n is
 1. 10.The compound of claim 9, having a structure which is a member selectedfrom the group consisting of:

wherein R⁴ is a member selected from the group consisting of H and CH₃.11. The compound of claim 4, having a structure which is a memberselected from the group consisting of:

wherein A¹, A², A³ and A⁴ are each independently selected from the groupconsisting of O, S, N(R^(b))_(b), and C(R^(b))_(b)(R^(c)); a is aninteger selected from the group consisting of 0 to 2; b is an integerselected from the group consisting of 0 to 1; R^(b) and R^(c) aremembers independently selected from the group consisting of H, halogen,CF₃, CN, OR¹⁴, SR¹⁴, NR¹⁵R¹⁶, NR¹⁵S(O)₂R¹⁴, NR¹⁵C(O)R¹⁴, S(O)₂R¹⁴, acyl,C(O)OR¹⁴, C(O)NR¹⁵R¹⁶, S(O)₂NR¹⁵R¹⁶, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl and substituted orunsubstituted heterocycloalkyl; each R¹⁴, R¹⁵ and R¹⁶ is a memberindependently selected from the group consisting of H, acyl,substituted, or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl,wherein two of R¹⁴, R¹⁵ and R¹⁶, together with the atoms to which theyare attached, are optionally joined to form a 3- to 7-membered ring,which optionally includes from 1 to 3 heteroatoms.
 12. A pharmaceuticalcomposition comprising a compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier, vehicle or diluent.
 13. A method for treating or preventing aneurological disorder, said method comprising administering to a subjectin need thereof a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt or solvate thereof. 14.The method of claim 13, wherein said neurological disorder is a memberselected from the group consisting of substance abuse, fibromyalgia,pain, sleep disorder, attention deficit disorder (ADD), attentiondeficit hyperactivity disorder (ADHD), restless leg syndrome,depression, schizophrenia, anxiety, obsessive compulsive disorder, panicdisorder, posttraumatic stress disorder, premenstrual dysphoria, andneurodegenerative disease.
 15. The method of claim 14, wherein saidsleep disorder is sleep apnea.
 16. The method of claim 14, wherein saidpain is neuropathic pain.
 17. A method for treating or preventing aneating disorder, said method comprising administering to a subject inneed thereof a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt or solvate thereof.
 18. Amethod for treating or preventing obesity, said method comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltor solvate thereof.
 19. A method of inhibiting reuptake of at least onemonoamine from a cell, said method comprising administering to amammalian subject a compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof.
 20. The method of 19, wherein saidmonoamine is a member selected from group consisting of serotonin,dopamine and norepinephrine.
 21. A method of modulating one or moremonoamine transporter, said method comprising administering to amammalian subject a compound of claim 1, or a pharmaceuticallyacceptable salt or solvate thereof.
 22. The method of claim 21, whereinsaid monoamine transporter is a member selected from the groupconsisting of serotonin transporter (SERT), dopamine transporter (DAT)aminorepinephrine (NET) transporter.
 23. The method of claim 14,wherein, said substance abuse is abuse of a member selected fromcocaine, nicotine or a combination thereof.
 24. The method of claim 14,wherein said neurodegenerative disease is Parkinson's disease.
 25. Acompound having the formula:


26. A pharmaceutical formulation comprising a compound according toclaim 25 in combination with a pharmaceutically acceptable excipient.27. A compound having the formula:


28. A pharmaceutical formulation comprising a compound according toclaim 27 in combination with a pharmaceutically acceptable excipient.29. A compound having the formula:


30. A pharmaceutical formulation comprising a compound according toclaim 29 in combination with a pharmaceutically acceptable excipient.